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24 September 2015 EMA/801150/2015 Committee for Medicinal Products for Human Use (CHMP)

Assessment report

IONSYS

International non-proprietary name: fentanyl

Procedure No. EMEA/H/C/002715/0000

Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted.

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Assessment report EMA/801150/2015 /63

Table of contents

1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ..................................................................................... 7 1.2. Steps taken for the assessment of the product ........................................................ 8

2. Scientific discussion ................................................................................ 9 2.1. Introduction ........................................................................................................ 9 2.2. Quality aspects .................................................................................................. 11 2.2.1. Introduction.................................................................................................... 11 2.2.2. Active Substance ............................................................................................. 12 2.2.3. Finished Medicinal Product ................................................................................ 14 2.2.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 17 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 17 2.2.6. Recommendation(s) for future quality development ............................................. 17 2.3. Non-clinical aspects ............................................................................................ 18 2.3.1. Introduction.................................................................................................... 18 2.3.2. Pharmacology ................................................................................................. 18 2.3.3. Pharmacokinetics ............................................................................................ 19 2.3.4. Toxicology ...................................................................................................... 20 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 23 2.3.6. Discussion on non-clinical aspects ..................................................................... 23 2.3.7. Conclusion on the non-clinical aspects ............................................................... 24 2.4. Clinical aspects .................................................................................................. 24 2.4.1. Introduction.................................................................................................... 24 2.4.2. Pharmacokinetics ............................................................................................ 26 2.4.3. Pharmacodynamics .......................................................................................... 30 2.4.4. Discussion on clinical pharmacology ................................................................... 30 2.4.5. Conclusions on clinical pharmacology ................................................................. 32 2.5. Clinical efficacy .................................................................................................. 32 2.5.1. Dose response study(ies) ................................................................................. 32 2.5.2. Main studies ................................................................................................... 32 2.5.3. Discussion on clinical efficacy ............................................................................ 49 2.5.4. Conclusions on the clinical efficacy .................................................................... 52 2.6. Clinical safety .................................................................................................... 53 2.6.1. Discussion on clinical safety .............................................................................. 55 2.6.2. Conclusions on the clinical safety ...................................................................... 56 2.7. Risk Management Plan ........................................................................................ 56 2.8. Pharmacovigilance ............................................................................................. 59 2.9. Significance of paediatric studies .......................................................................... 59 2.10. Product information .......................................................................................... 60

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2.10.1. User consultation ........................................................................................... 60

3. Benefit-Risk Balance ............................................................................. 60

4. Recommendations ................................................................................. 61

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List of abbreviations

ºC degrees centigrade µ mu, a type of opioid receptor µA microampere µg microgram ADR adverse drug reaction AEs adverse events ALZA ASA

ALZA corporation; Mountain View, CA, USA American society of anesthesiologists

ASR ASMF

application site reaction Active substance master file

AUC area under the concentration-versus-time curve B BA

black bioavailability

BE bioequivalence BID twice daily (bis in die) BMI body mass index BP bpm CHMP

blood pressure beats per minute (heart rate), breaths per minute (respiratory rate) committee for medicinal products for human use

CI confidence interval cm centimetre Cmax maximum concentration CNS central nervous system CO2 COSTART CRF CRRD

carbon dioxide Coding Symbols for Thesaurus of Adverse Reaction Terms case report form clinically relevant respiratory depression

CV coefficient of variation dL E EC

decilitre elderly European commission

ECAT Electrically conductive adhesive tape EMA European medicines agency ENT EP ESRD ETS

ear, nose and throat European Pharmacopoeia end-stage renal disease E-TRANS (fentanyl HCl) system

ETSS E-TRANS separated system EU European union FDA FMEA

United States Food and Drug Administration failure modes and effects analysis

GCP good clinical practice GI GLP gm GMP h or Hr. HCl

gastrointestinal Good Laboratory Practice gram Good manufacturing practise hour hydrochloride

HCP HDPE

health care professional High density polyethylene

HPLC High performance liquid chromatography ICH International Conference on Harmonisation of Technical Requirements for Registration

of Pharmaceuticals for Human Use

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IFUD instructions for use and disposal IM intramuscular Incline Incline therapeutics, Inc. IONSYS IP

registered trademark for the Applicant’s proprietary iontophoresis drug delivery system intraperitoneal

IR Infrared ISR incurred sample reanalysis IV intravenous IVIVC in vitro/in vivo correlation J&J Johnson & Johnson JCAHO JMI

joint commission on accreditation of healthcare organizations Johnson Matthey Inc.

KF Karl Fischer titration kg kilogram l litre LC/MS/MS liquid chromatography tandem mass spectrometry LCD LDPE

liquid crystal display low density polyethylene

LED light-emitting diode LOQ limit of quantification MAA marketing authorization application MAH MAO

marketing authorization holder monoamine oxidase

mg milligram min minutes mL millilitre mm millimetre MSS n NaOH

medically supervised setting number or sample size Sodium hydroxide

ng nanogram NMR Nuclear Magnetic Resonance OAPR onset of analgesia/pain relief PACU PCA

post-anaesthesia care unit patient-controlled analgesia

pCO2 PD

end-tidal carbon dioxide tension pharmacodynamic(s)

PDCO EMA paediatric committee PET Polyethylene terephthalate Ph. Eur. European Pharmacopoeia PIP paediatric investigation plan PK PONV

pharmacokinetic(s) post-operative nausea and vomiting

QC QP

quality control Qualified person

q10min every 10 minutes RH relative humidity RIA radioimmunoassay RMP risk management plan RR SAE

respiratory rate serious adverse event

SC SD

subcutaneous standard deviation

SEM standard error of the mean SFTA System Functionality Apparatus SIS SmPC

self-initiation of the system summary of product characteristics

SpO2

arterial oxygen saturation determined by pulse oximetry

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SSEC separated system with enhanced controller t1/2 elimination half-life tmax time to maximum concentration TEAE treatment-emergent adverse event TID three times daily (ter in die) TLC Thin layer chromatography TTS transdermal therapeutic system US USP

United States United States Pharmacopoeia

VAS visual analogue scale vs. Versus

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1. Background information on the procedure

1.1. Submission of the dossier

The applicant Incline Therapeutics Europe Ltd submitted on 3 September 2014 an application for Marketing Authorisation to the European Medicines Agency (EMA) for IONSYS, through the centralised procedure under Article 3(2)(b) of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 15 March 2012. The eligibility to the centralised procedure under Article 3(2)(b) of Regulation (EC) No 726/2004 was based on demonstration of significant therapeutic innovation.

The applicant applied for the following indication:

IONSYS is indicated for the management of acute moderate to severe post-operative pain in adults for use in a hospital setting only.

The legal basis for this application refers to:

Article 8.3 of Directive 2001/83/EC - complete and independent application

The applicant indicated that fentanyl was considered to be a known active substance.

The application submitted is composed of administrative information, complete quality data, non-clinical and clinical data based on applicants’ own tests and studies and/or bibliographic literature substituting/supporting certain tests or studies.

Information on Paediatric requirements

Pursuant to Article 7 of Regulation (EC) No 1901/2006, the application included an EMA Decision P/0111/2014 on the agreement of a paediatric investigation plan (PIP).

At the time of submission of the application, the PIP P/0111/2014 was not yet completed as some measures were deferred.

Information relating to orphan market exclusivity

Similarity

Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No 847/2000, the applicant did not submit a critical report addressing the possible similarity with authorised orphan medicinal products because there is no authorised orphan medicinal product for a condition related to the proposed indication.

Scientific Advice

The applicant received Scientific Advice from the CHMP on 26 February 1999, 23 June 2011, 20 July 2011 and 29 September 2011. The Scientific Advice pertained to quality, non-clinical and clinical aspects of the

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dossier.

Licensing status

IONSYS was given a Marketing Authorisation in the United States on 22 May 2006.

1.2. Steps taken for the assessment of the product

The Rapporteur and Co-Rapporteur appointed by the CHMP were:

Rapporteur: Greg Markey Co-Rapporteur: Outi Mäki-Ikola

• The application was received by the EMA on 3 September 2014.

• The procedure started on 24 September 2014.

• The Rapporteur's first Assessment Report was circulated to all CHMP members on 12 December 2014. The Co-Rapporteur's first Assessment Report was circulated to all CHMP members on 12 December 2014.

• PRAC assessment overview, adopted by PRAC on 8 January 2015.

• During the meeting on 22 January 2015, the CHMP agreed on the consolidated List of Questions to be sent to the applicant. The final consolidated List of Questions was sent to the applicant on 23 January 2015.

• The applicant submitted the responses to the CHMP consolidated List of Questions on 21 May 2015.

• The following GMP inspection was requested by the CHMP and its outcome taken into consideration as part of the Quality/Safety/Efficacy assessment of the product:

A GMP inspection at one finished product manufacturing site in the USA was conducted between 17-21 November 2014.

• The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of Questions to all CHMP members on 26 June 2015.

• PRAC advice and assessment overview, adopted by PRAC on 9 July 2015.

• During the CHMP meeting on 23 July 2015, the CHMP agreed on a list of outstanding issues to be addressed in writing and by the applicant.

• The applicant submitted the responses to the CHMP List of Outstanding Issues on 21 August 2015.

• The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the list of outstanding issues to all CHMP members on 1 September 2015.

• PRAC advice and assessment overview, adopted by PRAC on 10 September 2015.

• During the meeting on 24 September 2015, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, issued a positive opinion for granting a Marketing Authorisation to IONSYS.

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2. Scientific discussion

2.1. Introduction

Fentanyl is a synthetic opioid related to the phenylpiperidine class of compounds. It is a highly sensitive μ-receptor agonist and is about 100 times more potent than morphine as an analgesic. Opioids exert their therapeutic effects by mimicking the action of endogenous opioid peptides at opioid receptors. Effects on both local neurons and intrinsic pain-modulating circuitry lead to analgesia and other therapeutic effects as well as undesirable side-effects, the most serious of which is respiratory depression.

Patient-controlled analgesia (PCA) is an important technique which permits patients to self-administer small doses of opioids such as fentanyl, morphine, hydromorphone or pethidine, on an ‘on-demand’ basis to manage pain. It was originally conceived and developed to minimise the effects of pharmacokinetic and pharmacodynamic variability among individual patients. Patient-controlled analgesia has subsequently become a safe and effective mainstay of post-surgical maintenance analgesia worldwide, instituted once the initial control of the patient’s post-operative pain has been achieved via other methods.

IONSYS® (fentanyl transdermal system) is an iontophoretic transdermal system containing fentanyl, a potent mu-receptor opioid agent commonly used for analgesia. Each IONSYS system consists of two parts that are snapped together by the health care professional (HCP) just prior to application to the upper outer arm or chest of the patient. Each assembled system contains 10.8 mg fentanyl hydrochloride (HCl) equivalent to 9.7 mg of fentanyl and delivers 40 μg fentanyl per dose. Each system is designed to deliver up to a maximum of 240 μg per hour (up to 6 doses each of 10 minutes duration) and up to a maximum of 80 doses within a 24-hour period.

The clinical development program for IONSYS was originally conducted with an integrated system product configuration, initially developed by ALZA, a subsidiary of Johnson & Johnson (J&J), in which both the electronics and drug hydrogels were contained within a single housing. This product configuration was referred to as the E-TRANS System or ETS. A Marketing Authorisation Application (MAA) for IONSYS was originally submitted in July 2004 (EMEA/H/C/612) by Janssen-Cilag (a subsidiary of J&J). In January 2006, IONSYS received a European marketing licence, based on a positive benefit and risk profile demonstrated in 2144 adult postoperative patients in 20 clinical studies and 340 healthy volunteers in 11 pharmacokinetic (PK) studies. The product was marketed in select European countries beginning in January 2008. However, the product was voluntarily recalled by J&J in September 2008 due to observations of corrosion on the printed circuit board that could have potentially resulted in overdose due to self-initiation (i.e., doses delivered without dose initiation by the patient). No instances of self-initiation were reported.

A second generation IONSYS was developed by J&J to provide enhanced stability and to address the issue resulting in withdrawal of the system from the market in 2008. This version was a separated system consisting of a Controller and a Drug Unit and is referred to as the E-TRANS Separated System or ETSS in the current MAA. The Controller contained the same core electronics as the ETS, and the Drug Unit contained the same formulation. The Controller and Drug Unit were assembled by the HCP prior to use. The ETSS was shown to be bioequivalent to the ETS in a crossover PK study (C-2006-036). The ETSS was never marketed anywhere in the world.

Incline Therapeutics, Inc. acquired the worldwide rights to IONSYS from J&J in June 2010. Incline conducted a comprehensive Product Risk Analysis and Fault Tree Analysis to identify all potential failure modes that could lead to unintended fentanyl delivery to the patient. Incline has completed the development program to

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eliminate corrosion and all other potential causes of unintended fentanyl delivery. The Incline product consists of a Controller with enhanced electronics and a Drug Unit which are assembled by the HCP prior to use. This enhanced version of IONSYS, for which approval is being sought, is referred to in the current MAA as the Separated System with Enhanced Controller or SSEC.

EMA Advice:

Member State Advice:

The Applicant asked for Scientific Advice on this issue and the CHMP agreed that the changes to the IONSYS system adequately mitigated the risks of corrosion assuming successful test results and compliance with appropriate regulatory standards (Scientific Advice letter EMA/CHMP/SAWP/424689/2011). It was also confirmed in subsequent correspondence (clarification letter dated 20 July 2011, Module 1.2, Annex 5.14.) that the controller would not be considered a medical device under the Medical Devices Directive 93/42/EEC since it is to be placed on the market in such a way that the device and the medicinal product form a single integral product which is intended exclusively for use in the given combination and which is not reusable. IONSYS is therefore governed by Directive 2001/83/EC and CE marking is not required. As suggested by the

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CHMP in the Scientific Advice, study PK2011-001 was performed to provide evidence of equivalence of the SSEC with the ETS.

2.2. Quality aspects

2.2.1. Introduction

The finished product is presented as a transdermal system which contains fentanyl hydrochloride, equivalent to 9.7 mg of fentanyl, and delivers 40 µg fentanyl per dose. It will operate for 24 hours after the system is assembled or for 80 doses (corresponding to 3.2 mg fentanyl /24 hours), whichever comes first, and then becomes inoperative.

Ionsys was previously authorised in January 2006 (EMEA/H/C/0612) but was recalled from the market in September 2008 following the detection of corrosion since this may have led to the product self-actuating. The marketing authorisation was suspended in January 2009 and expired in January 2011. This current application is for an improved presentation where the electronics and hydrogels are separated prior to use in order to remove the likelihood of corrosion and malfunction.

The transdermal system is composed of an electronic controller and a drug unit with two hydrogels.

The controller is white with the identifier ‘IONSYS®’ and has a digital display, a light window, and a recessed dose activation button.

The drug unit is blue on the side that connects to the controller and has a red bottom housing containing the hydrogels, one of which contains the fentanyl hydrochloride active substance. The drug unit consists of four main elements: interface module; bottom housing assembly; skin adhesive; and release liner.

Ingredients of the bottom housing assembly are:

- bottom housing unit: glycol-modified polyethylene terephthalate

- anode hydrogel: polacrilin, purified water, sodium hydroxide, polyvinyl alcohol

- cathode hydrogel: purified water, sodium chloride, sodium citrate, polyvinyl alcohol, anhydrous citric acid, cetylpyridinium chloride

- anode electrode: layers of silver foil and electrically conductive adhesive tape

- cathode electrode: layers of polyisobutylene/silver chloride/carbon black composite material, silver foil, and electrically conductive adhesive tape

- skin adhesive: polybutene, polyisobutylene, and rosin ester

- protective liner: polyester film coated on one side with silicone

Each transdermal system is packaged in a sealed thermoform tray. The tray contains one controller and one sachet containing a drug unit. The sachet foil is comprised of a lamination of nylon, aluminium foil and a heat seal layer of a copolymer of polyethylene and polymethacrylic acid. Each tray is packaged in a folding cardboard carton.

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2.2.2. Active Substance

General information

The chemical name of fentanyl hydrochloride is N-Phenyl-N-[1-(2-phenethyl)-4-piperidinyl] propanamide hydrochloride and it has the following structure:

Fentanyl HCl is a white to off-white solid, soluble in water and methanol. As the drug is completely dissolved in the proposed formulation, studies of polymorphism and particle size were not deemed necessary.

The information on the active substance is provided according to the Active Substance Master File (ASMF) procedure.

Manufacture, characterisation and process controls

The active substance is sourced from one supplier and manufactured by three manufacturing sites (two of them are alternative manufacturing sites for the intermediate FC1002). The active substance is synthesized in four main steps using commercially available well defined starting materials with acceptable specifications.

Adequate in-process controls are applied during the synthesis. The specifications and control methods for intermediate products, starting materials and reagents have been presented.

Detailed information on the manufacturing of the active substance has been provided in the restricted part of the ASMF and it was considered satisfactory.

The structure of the active substance has been confirmed using elemental analysis, IR, H1 NMR and C13 NMR. The active substance has a non-chiral molecular structure. The characterisation of the active substance and its impurities are in accordance with the EU guideline on chemistry of new active substances. Potential and actual impurities including genotoxic impurities were well discussed with regards to their origin and characterised. Genotoxic impurities are controlled in compliance with the Guideline on the Limits of Genotoxic Impurities EMEA/CHMP/QWP/251344/2006.

The active substance is packaged in double low density polyethylene bags inside an HDPE container. The LDPE bag is in immediate contact with the active substance complies with the European Commission Regulation EC 10/2011 as amended and European Pharmacopoeia.

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Specification The active substance specification includes tests for: appearance, identity (IR, HPLC, chloride identification), assay (HPLC), impurities (HPLC), loss on drying (Ph. Eur.).

There is no Ph. Eur. monograph for fentanyl hydrochloride although there are Ph. Eur. monographs for the fentanyl citrate and fentanyl base.

The limits applied to the fentanyl hydrochloride related substances are within those set by the Ph. Eur. monographs for fentanyl citrate and fentanyl base.

The omission of a specific limit for diisopropyl ether solvents used in the manufacture of the drug substance has been adequately justified. However, the justification provided by the applicant at the time of opinion for the absence of control of the toluene and benzene content in the active substance specification is not considered fully acceptable. Therefore, the CHMP recommends the applicant to demonstrate on the first 3 consecutive industrial scale batches of the final active substance that the content of toluene is not more than 10 % of the acceptable concentration limit stated in the ICH/VICH guideline on impurities: residual solvents and that benzene content is not more than 30 % of the specified limit, using a validated analytical methods. Otherwise a control of toluene and/or benzene content should be included in the active substance specification with a variation.

The analytical methods used have been adequately described and non-compendial methods appropriately validated in accordance with the ICH guidelines. Satisfactory information regarding the reference standards used for assay and impurities testing has been presented.

Three certificates of analysis of two active substance batches tested by the finished product manufacturer have been submitted. In addition, batch analysis data on six batches of the active substance tested by active substance manufacturer have been provided. The batch analysis results analysed by finished product manufacturer and active substance manufacturer are similar. All the results are within the specifications and consistent from batch to batch. Therefore, it is considered acceptable that the finished product manufacturer analysed only two batches of active substance.

Stability

Stability data were provided on three batches of active substance from the proposed manufacturer stored in the intended commercial package for 24 months under long term conditions at 25 ºC / 60% RH and for up to 6 months under accelerated conditions at 40 ºC / 75% RH according to the ICH guidelines.

Additional stability data performed on the active substance stored in the initial commercial packaging (not proposed for marketing) -amber glass bottles with a Screw Top with a phenolic lid with polyvinyl liner- were also provided.

The following parameters were tested: appearance, assay (HPLC), impurities (HPLC), water content (KF). The analytical methods used were the same as those used for release by the ASMF holder and were stability indicating. All tested parameters were within the proposed specifications except for one batch. For this batch the accelerated study was discontinued as it did not meet the specification for appearance at the 3-month time point. The long-term stability study for this batch, however, is still ongoing and has been successfully completed through the 24 month time point. This batch, manufactured in 2005 and originally packaged in amber glass, was re-packaged in the new HDPE packaging in 2011, and the stability study was re-initiated

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under long-term and accelerated conditions. Therefore it was concluded that the observed out of specification results is not significant and does not pose any concern.

The stability data is supported by a forced degradation study indicating that the active substance was stable to light, heat and alkali conditions. Degradation was seen when subjected to heat and acid, or heat and oxidising conditions.

The stability results indicate that the active substance manufactured by the proposed supplier is sufficiently stable. The stability results justify the proposed 24 month retest period in the proposed container.

2.2.3. Finished Medicinal Product

Description of the product and pharmaceutical development The proposed finished product is a transdermal system that consists of a controller (device component) and a drug unit containing fentanyl hydrochloride.

The drug unit contains:

- an interface module (IM)

- a bottom housing assembly that includes hydrogels with the fentanyl hydrochloride in the anode hydrogel

- a skin adhesive

- a release liner

The drug unit is packaged in a sealed aluminium foil sachet. The drug unit sachet and the controller are packaged in a sealed plastic tray along with two leaflets.

The purpose of the product development was to design a safe, non-invasive and convenient alternative to conventional intravenous (iv) patient-controlled analgesia (PCA) by using iontophoresis-based transdermal delivery of fentanyl through intact skin.

The original Ionsys transdermal system, referred as ETS in this MAA, was authorised in January 2006 (EMEA/H/C/0612). It was developed to provide transdermal PCA over a period of 24 hours over which a maximum of 80 doses could be delivered. Each dose delivered 40μg of fentanyl over 10 minutes during which time the system was locked out. The system was deactivated after 24 hours or after 80 doses had been used up. The maximum nominal amount of fentanyl that could be administered from a single system over 24 hours was 3.2 mg. It was an integrated system in which the electronics were exposed to high humidity from the hydrogels during manufacturing and storage. Although the marketed product included a humidity regulating absorber to prevent condensation, after marketing it was noticed that this did not avoid exposure of electronics to high humidity during manufacturing and storage, and could pose a risk of corrosion and

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malfunction. As a result, the finished product was recalled from the market in September 2008. The marketing authorisation was suspended in January 2009 and expired in January 2011.

An enhanced version of the transdermal system, referred to as the Separated System with Enhanced controller (SSEC) was therefore developed to mitigate the risk of overdose due to corrosion or any other cause. The SSEC is a separated version of the ETS transdermal system in which the active substance unit containing the hydrogels and the device portion (electronics) are manufactured separately and packaged individually for storage. The SSEC operates on the same principle as the ETS. The SSEC drug unit contains the same formulation (hydrogels and electrodes) and the same skin-contacting materials as the ETS. In the SSEC, the top housing of the ETS is replaced by the interface module (IM) and a separate controller. The IM is a plastic injection molded part with gold plated connectors that provides electrical and mechanical connection between the drug unit and the controller. The controller of the SSEC was designed based on experience with the ETS. The electronics in the SSEC controller are different from the ETS which was used for the original clinical development program. Enhanced electronics were developed to eliminate the potential for unintended fentanyl delivery, and the blinking light of the ETS version was replaced with a digital display to show the number of doses delivered to the patient. A comparison of the SSEC and ETS electronics has been provided. The controller provides the same drug delivery parameters (dose current, dose duration, dose lock-out, and maximum duration of use) as the ETS.

Prior to use by the patient, the Health Care Professional (HCP) will remove the drug unit from the sachet and attach it to the controller. The HCP will then remove the protective plastic film (release liner) from the skin adhesive of the assembled SSEC before applying the SSEC to the patient. After the SSEC is assembled, the HCP and patient will use the system in the same way as the ETS system. Once assembled, the controller and drug unit cannot be separated. If forced apart, the controller electronics are automatically deactivated and are designed such that they cannot be used again. In this case, the device will shutdown rather than re-set.

The differences between ETS transdermal system and SSEC transdermal system have been adequately described and justified. The risk of corrosion and malfunction associated with ETS version are considered to be addressed by this new SSEC version.

The key components responsible for fentanyl delivery are: anode hydrogel, cathode hydrogel and controller.

Compositions of the drug unit and controller parts have been provided.

All excipients are well known pharmaceutical ingredients and their quality is compliant with Ph. Eur standards. There are no novel excipients used in the finished product formulation. The complete list of excipients is included in section 6.1 of the SmPC and in paragraph 2.1.1 of this report.

Controller technical documentation has been provided. The algorithm defining the use of the device has been described. The applicant has taken into account in an appropriate manner harmonized or equivalent international standards and other suitable methods to demonstrate compliance of the controller unit with the essential requirements of Directive 93/42/EEC.

Overall the data in the dossier related to ETS―SSEC comparability (pharmaceutical, electro-mechanical, manufacturing) demonstrate that the changes made to facilitate the SSEC design have resulted in the pharmaceutical equivalence of the SSEC with the ETS. Comparison of in-vitro drug release profile from ETS and SSEC was provided. These data were generated using the same in-vitro drug release equipment and test method that was validated for the ETS and for the SSEC. The results demonstrate that the drug release from the SSEC transdermal system is equivalent to that from the ETS transdermal system.

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The primary packaging of the transdermal system is a thermoformed HDPE tray and a PET/Aluminium foil heat sealed lid. The tray contains one controller and one sachet containing a drug Unit. The primary packaging of the drug unit is a sachet foil comprised of a lamination of nylon, aluminium foil and a heat seal layer of a copolymer of polyethylene and polymethacrylic acid. The material of drug unit primary packaging complies with EC requirements. The choice of the container closure system has been validated by stability data and is adequate for the intended use of the product.

Manufacture of the product and process controls

The manufacturing process consists of six main steps: anode and cathode hydrogel mixing, bottom housing assembly including filling with hydrogels, hydrogel curing in the bottom housing assembly (BHA), drug unit assembly, drug unit packaging into sachet and drug unit co-packaging with the controller to produce the finished product. The drug unit is manufactured using the same process and equipment that was used to manufacture the ETS. The only new component in the drug unit of the SSEC compared to the ETS is the interface module. The process is considered to be a non-standard manufacturing process. The critical process parameters and in-process controls are adequate for this type of manufacturing process and pharmaceutical form. Manufacturing of controller part has also been described.

The manufacturing process of the drug unit has been validated on three production scale batches. Holding times were validated. It has been demonstrated that the manufacturing process is capable of producing the finished product of intended quality in a reproducible manner.

Product specification

The finished product release specification include appropriate tests for this kind of dosage form : appearance of drug unit and finished product, identification (TLC and HPLC), fentanyl assay (HPLC), fentanyl impurities (HPLC), cetylpyridinium chloride assay (HPLC) , adhesive testing (tensil tester), pH of hydrogels, conductivity of hydrogels, microbiological purity (Ph. Eur.), delivered dose (System Functionality Test Apparatus (SFTA), HPLC), Mean Interdose Current (SFTA), Number of Doses (SFTA), Dose charge (SFTA).

Electrical parameters such as output current and the release of fentanyl are monitored using a System Functionality Apparatus (SFTA). The released fentanyl from each actuation is collected in a citrate/sodium chloride buffer containing polysorbate and is then determined by a HPLC method.

All analytical methods used have been adequately described and appropriately validated in accordance with the ICH guidelines. Satisfactory information regarding the reference standards used for assay and impurities testing has been presented.

Batch analysis results including results for three production scale batches are provided confirming the consistency of the manufacturing process and its ability to manufacture to the intended product specification.

Stability of the product

Stability data were provided for several batches of finished product, including three production scale batches, stored under long term conditions for 13 months at 25 ºC / 60% RH and for up to 6 months under accelerated conditions at 40 ºC / 75% RH according to the ICH guidelines. The batches of medicinal product are identical to those proposed for marketing and were packed in the primary packaging proposed for marketing.

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Samples were tested according to the release specifications. The analytical procedures used are stability indicating. No significant changes have been observed during stability studies in any of the parameters tested.

Based on available stability data, the 24 month shelf-life, with the storage precaution “Do not store above 25°C. Do not refrigerate or freeze” and the statement “Use immediately after opening” as stated in the SmPC are acceptable.

Adventitious agents

No excipients derived from animal or human origin have been used.

2.2.4. Discussion on chemical, pharmaceutical and biological aspects

An enhanced version of the Ionsys ETS transdermal system (authorised in January 2006 (EMEA/H/C/0612), suspended in January 2009 and expired in January 2011) was developed to mitigate the risk of overdose due to corrosion and malfunction encountered with the ETS version. The Ionsys SSEC transdermal system is a separated version of the ETS transdermal system in which the active substance unit containing the hydrogels and the device portion (electronics) are manufactured separately and packaged individually for storage. The SSEC drug unit contains the same formulation (hydrogels and electrodes) and same skin-contacting materials as the ETS. In the SSEC, the top housing of the ETS has been replaced by the IM and a separate controller. The differences between ETS transdermal system and SSEC transdermal system have been adequately described and justified. The risk of corrosion and malfunction associated with ETS version are considered to be addressed by this new SSEC version. The SSEC operates on the same principle as the ETS. It provides transdermal patient controlled analgesia over a period of 24 hours over which a maximum of 80 doses could be delivered. Each dose delivers 40μg of fentanyl over 10 minutes during which time the system would be locked out. The system deactivates after 24 hours or after administration of 80 doses. The maximum nominal amount of fentanyl that can be administered from a single system over 24 hours is 3.2 mg. In-vitro drug release profiles of the SSEC and ETS were comparable. Information on development, manufacture and control of the active substance and finished product has been presented in a satisfactory manner. The results of tests carried out indicate consistency and uniformity of important product quality characteristics, and these in turn lead to the conclusion that the product should have a satisfactory and uniform performance in clinical use.

At the time of the CHMP opinion, there was a minor unresolved quality issue related to the active substance specifications having no impact on the Benefit/Risk ratio of the product.

2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects

The quality of this product is considered to be acceptable when used in accordance with the conditions defined in the SmPC. Physicochemical and biological aspects relevant to the uniform clinical performance of the product have been investigated and are controlled in a satisfactory way.

2.2.6. Recommendation(s) for future quality development

In the context of the obligation of the MAHs to take due account of technical and scientific progress, the CHMP recommends the following points for investigation:

the applicant should demonstrate on the first three consecutive industrial scale batches of the final active

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substance that the content of toluene is not more than 10 % of the acceptable concentration limit stated in the ICH/VICH guideline on impurities: residual solvents and, that benzene content is not more than 30 % of the specified limit, using validated analytical methods. Otherwise a control of toluene and/or benzene content should be included in the active substance specification with a variation.

2.3. Non-clinical aspects

2.3.1. Introduction

2.3.2. Pharmacology

Primary pharmacodynamic studies

Fentanyl has been extensively described as a potent opioid analgesic and the applicant has provided a summary of the relevant non-clinical literature to establish the applicability of their transdermal product. In vitro studies have demonstrated that fentanyl binds with a higher affinity to µ opioid receptors as compared to κ- or δ-opiate receptors. In vivo pharmacodynamics has been described in mice and rats with clear anti-nociceptive and analgesic effects, with an increased margin for safety compared to other opioid analgesics such as morphine. Given the well characterised pharmacology of fentanyl, the applicant’s review is acceptable.

Secondary pharmacodynamic studies

No dedicated secondary pharmacology studies have been performed and this is acceptable given the extensive clinical use of fentanyl.

Safety pharmacology programme

The safety pharmacology of fentanyl as a component of IONSYS has been extensively investigated. As has been highlighted in the dossier many of these reports/studies were completed prior to Good Laboratory Practice (GLP) compliance standards and are in many instances based on older references. A number of more recent reviews have been introduced into the overall discussion. The secondary adverse effects of opioids are already well known and the review supplied further discusses the potential of fentanyl to cause respiratory depression, constipation, physical dependence, and euphoria. No new safety concerns are expected in the use of fentanyl in the IONSYS product over and above that already established with other formulations and presentations for fentanyl.

Pharmacodynamic drug interactions

No pharmacodynamic interaction studies have been completed. The use of fentanyl with concomitant medication is already well-established so the absence of these studies is acceptable. Concomitant use of other CNS depressants, including other opioids, sedatives or hypnotics, general anaesthetics, phenothiazines, tranquillisers, skeletal muscle relaxants, sedating antihistamines and alcoholic beverages are noted to produce additive depressant effects. Hypoventilation, hypotension and profound sedation or coma may occur. Use of fentanyl with monoamine oxidase (MAO) inhibitors within 14 days is not recommended due to

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the potential for potentiation of the effects of opioid analgesics when administered MAO inhibitors. There are appropriate warnings in the SmPC.

2.3.3. Pharmacokinetics

The pharmacokinetics (PK) of fentanyl delivered by transdermal, subcutaneous (SC) and intravenous (IV) administration are well documented, and the applicant has described the PK characteristics using a variety of literature sources in addition to the use of legacy study reports with fentanyl. With respect to transdermal delivery of fentanyl, studies have been completed previously using hairless rat skin, both in vitro and in vivo, exploring the advantages of using iontophoresis (application of an electrical field across the skin) and electroporation (application of high voltage external field pulses) on improving fentanyl drug absorption.

Literature references are provided to discuss the analytical methods used to detect plasma levels of fentanyl. These published studies are not GLP studies however are based upon the techniques used by Janssen Research for the initial studies with fentanyl. In addition the applicant has described methodology used to quantify fentanyl in the mouse dermal repeat-dose toxicity studies.

Fentanyl absorption has been described from both a transdermal and intravenous perspective. The transdermal data are obviously more relevant for this product and this was examined using hairless rat skin preparations, examining the influence of iontophoresis on increasing skin penetration. Penetration increased with iontophoresis compared to passive diffusion in the in vitro skin model, and this was confirmed with increased plasma levels of fentanyl when administered to hairless rats using iontophoresis. Electroporation also led to increased exposure to fentanyl. This data supports the concept of using an electrical current to deliver dosing of fentanyl via the transdermal route.

Intravenous exposure of fentanyl demonstrates the rapid absorption and elimination of fentanyl, half-life in rats was 8 minutes, 3 minutes in rabbits and dogs and <2 minutes in humans. The rapid reduction in exposure is mainly due to rapid uptake to tissues and its metabolism in the liver.

Distribution of fentanyl has been described using both in vitro and in vivo methods. There is a high level of plasma protein binding ranging from 84% in humans to 69% in mice, although there is consistency of 70-80% binding across each species. Binding is predominantly to albumin, but is also seen with α1-acid glycoprotein and lipoproteins. Fentanyl appears to be readily taken up by blood in a dose-dependent manner, binding mainly to haemoglobin.

Tissue distribution has briefly been reviewed; fentanyl is taken up rapidly, predominantly to the brain but is also stored in fat, muscle and liver. Fentanyl has been shown to pass though the placenta and may be distributed to breast milk. Adequate warnings are included in the SmPC.

In the initial review there was little or no evidence has been supplied here to acknowledge the distribution of fentanyl following transdermal delivery, as will be the case for the use with IONSYS. The applicant has provided some further discussion on the issue of potential accumulation of fentanyl into fat tissue. It has been described that delivery via the IONSYS device allows for an active iontophoretic transdermal delivery of fentanyl resulting in rapid migration through the skin and into the systemic circulation. This means that there is no accumulation of fentanyl ions in the skin or subcutaneous fat tissue. This is supported by the clinical pharmacokinetic data that suggests that parameters are similar between intravenous and IONSYS (transdermal) delivery with rapid absorption of the fentanyl dose.

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The differences between traditional transdermal delivery systems and that provided by the IONSYS system have been given in more detail. There is relatively rapid uptake of fentanyl when using the IONSYS delivery; similar pharmacokinetic parameters are suggested between IV and IONSYS delivery routes. Half-lives are suggested to be 12.99 hr for IV and 11.04 hr for IONSYS. As a result the applicant argues that a shorter period of 24 hours between removal of the device and the initiation of breast-feeding is justified as highlighted in the SmPC.

Metabolism of fentanyl has been examined in mice, rats, guinea pigs, rabbits, dogs, sheep and human liver microsomes. Much of what has been described is from legacy study reports by Janssen from 20 years ago. Metabolism occurs mainly by oxidative N-dealkylation, but also occurs by hydroxylation and glucoronidation. No detailed discussion of metabolism at the skin has been provided however it is suggested that it is absorbed unchanged, before distribution and subsequent liver metabolism. The discussion provided for metabolism are relatively brief, however from the non-clinical perspective this could be accepted given the well established clinical use of this active substance and higher exposure levels. Although briefly mentioned in the applicant’s overview, it is unclear from the discussions provided what, if any, activity can be attributed to any of the metabolites of fentanyl, however this was further discussed in the pharmacology written summary.

Excretion has been adequately described. Elimination is via urine and faeces, but has also been detected in animal breast milk.

Pharmacokinetic drug interactions have been reviewed using to in vitro studies with human liver microsomes in which potential interaction with up to 55 compounds are described. Fentanyl is extensively metabolised by CYP3A4 and so interactions with inhibitors of this enzyme have potential to increase fentanyl plasma concentrations or extend exposure in vivo. The applicant has included warning to this effect in the SmPC.

2.3.4. Toxicology

Single dose toxicity

For acute toxicity a number of legacy studies have been reported with fentanyl using a variety of routes of administration, including subcutaneous. The main findings relate to excessive opioid-like effects – CNS effects, decreased activity, convulsions, tremors, loss of righting reflex, sedation and respiratory depression. The applicant also completed two GLP compliant studies in mice and rats using the intravenous route, confirming the effects already established with fentanyl. These studies determined lethal dose in 50 percent of animals to be 12.3 mg/kg in mice and 2.3 mg/kg in rats. Med

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Repeat dose toxicity

Repeat dose toxicity studies were presented from a variety of routes of administration, and species. Dermal toxicity has been presented in the mouse and rabbit. Further studies are also provided in the rat (SC, IM and IV) and dog (IV) to provide added support for systemic exposure with fentanyl. Concerning the dermal repeat dose toxicity studies, findings were related to pharmacological effects of opioids, with weight loss and CNS effects prevalent in the mouse and in the rabbit the adverse effects were limited to skin changes hyperkeratosis, acanthosis and sub-acute dermatitis indicating more of an irritation potential.

Genotoxicity

Genotoxicity was examined in a range of GLP in vitro and a single in vivo micronucleus study. A variation was observed in the mouse lymphoma study in the presence of S9, however once repeated the increase concern for increased mutation could not be replicated to the same extent. Results from the Ames and chromosome aberration studies and the micronucleus test indicate that fentanyl is not mutagenic. This is supported.

Carcinogenicity

The applicant has provided a long term carcinogenicity study with fentanyl in rats using daily SC administration up to 100 µg/kg/day. Although findings of pituitary adenomas (males and females), and mammary gland fibroadenomas and carcinomas (females) were observed, these appeared in all dose groups at comparable levels so was not considered to be related to treatment.

To further support the rat study a 26 week dermal alternative bioassay in Tg.AC transgenic mice has been reported. No evidence of increased neoplastic risk was identified, and so it is agreed that fentanyl shows no carcinogenic potential, and the risks of short term treatment with the IONSYS product would in any case be negligible given the low dose and treatment duration (up to 72 hrs).

Reproduction Toxicity

Two study reports are provided evaluating fertility and early embryonic development in rats following continuous intravenous infusion with fentanyl in both sexes. There are no adverse effects for fertility for either male or female rats. NOAEL in male rats is 0.4 mg/kg, and in females this is 0.025 mg/kg for maternal effects and 0.4 mg/kg for developmental effects.

In addition to these two studies, two published references are provided to further describe the in vitro effects of fentanyl on fertilisation and subsequent cell division in sea urchin eggs and an in vivo study in rats using SC continuous infusion using implanted osmotic minipumps.

Five study reports are provided evaluating embryo-fetal development in rats (IV, SC) and in rabbits (IV infusion). No teratogenic effects were detected in any of the five studies completed in rats or in rabbits. The most relevant finding is that of loss of maternal weight gain (rats and rabbits) and decreased pup weight (rats).

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In a pre- and post-natal developmental toxicity study all animals survived. At dosages of 0.025 and 0.1 mg/kg/day, neither maternal toxicity nor adverse effects on the litter were demonstrated. At 0.4 mg/kg, slight maternal toxicity was evidenced by a marginal decrease in body weight. NOAELs are 0.1 mg/kg for the F0 and F1 generation and 0.4 mg/kg for the F2 generation. Margins of safety for the high dose 0.4 mg/kg/day; Cmax 6.2 ng/mL), is at least 3 fold the human plasma level (2 ng/mL), although this is less than one for the 0.1 mg/kg level (Cmax 1.5 ng/mL).

Toxicokinetic data

Toxicokinetics (TK) was examined in a number of the legacy toxicity studies – these were conducted in mice (dermal), rats (SC and IV), and rabbits (dermal and IV). The higher safety factors (>1.5) are more apparent in the systemic exposure studies in rats, i.e. from the 5 week IV study and 3 month SC study, with the exception of the rat and rabbit developmental studies which either fentanyl plasma levels were too low to be detected or the safety factor to humans was below 1. The TK data is far from ideally presented in the dossier, however it is acknowledged that previous clinical exposure to fentanyl over and exceeds anything that is expected in this IONSYS preparation.

Local Tolerance Local tolerance has been studied with single and repeat-dose administration of IONSYS and using different anode and cathode hydrogel formulations and current densities. In addition, several studies were conducted in guinea pigs to evaluate the sensitisation potential of constituents of the IONSYS hydrogels and the adhesive.

A number of skin irritation studies have now been completed to assess the potential of the hydrogel formulation to sensitise the skin. Studies were completed in the rabbit and on hairless guinea pigs using a variety of formulations. Most importantly the final clinical product was used on hairless guinea pigs, and rabbits in this study in which the hydrogel was detected to be a mild irritant in both species. It was also established that use of a polymeric buffer – polacrilin – did not increase the skin irritation potential to any great extent. Animals were treated with placebo hydrogel, fentanyl hydrogel and fentanyl hydrogel with an electrical current and were then topically induced. All three preparations demonstrated mild irritation, and there was no increased discomfort in groups given electrically-assisted delivery of fentanyl.

The excipients used in the hydrogel have been adequately characterised and described in the non-clinical overview. Dermal sensitisation studies have been completed and reveal that the bactericidal agent (Cetylpyridinium chloride (CPC)), the buffer (Polacrilin) nor the adhesive act in a manner to exacerbate any skin irritation that may occur when administered IONSYS.

Other toxicity studies

No non-clinical studies have been conducted in juvenile animals during the development of IONSYS. No relevant studies have been identified in the published literature.

Tests to examine the biocompatibility of the IONSYS components (the silver foil used in the electrodes, the top (upper) housing: blue, and red, the bottom (lower) housing: red and blue, the electrically-conductive adhesive tape, PIB/silver chloride/carbon black electrode material and the adhesive were carried out. No concerns raised in respect to any of the components used.

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Abuse liability has been reviewed and concerns related to the use of this product are limited given its intended clinical use. Abuse potential of fentanyl has been adequately reviewed.

Literature data has been provided to examine the potential pharmacological activity of fentanyl metabolites, norfentanyl, α hydroxyfentanyl and para hydroxy fentanyl. α hydroxyfentanyl and para hydroxy fentanyl show some limited activity in an in vitro assay, and an in vivo tail withdrawal test (4-hydroxy-phenethylfentanyl or para hydroxy fentanyl). Although activity is less than the parent compound, the minor metabolite, para hydroxy fentanyl demonstrates similar activity to morphine. This metabolite is predominantly found in the guinea pig, rat and mouse and has not been detected as a human metabolite, and so a concern for clinical safety is negligible.

Two GLP studies were conducted to explore potential adverse effects of the impurity R004380. These studies were completed following acute intravenous administration to mice and rats. There was no evidence to suggest there was any additional adverse toxicity associated with the impurity R004380.

2.3.5. Ecotoxicity/environmental risk assessment

Summary of main study results Substance (INN/Invented Name): CAS-number (if available): PBT screening Result Conclusion Bioaccumulation potential- log Kow

Shake-flask method (Chemistry of Fentanyl; Kyowa Hakko Kogyo Co., Ltd., Japan, 1999)

2.96 Potential PBT (N)

Phase I Calculation Value Unit Conclusion PEC surfacewater , default or refined (e.g. prevalence, literature)

0.0004 µg/L > 0.01 threshold (N)

The applicant has provided a suitable review of the environmental risk implications of the use of fentanyl. The estimation of exposure (Phase I) of fentanyl does not raise concern with respect to the PEC action limit for surface water, this is 0.0004 µg/L, and so a Phase II assessment is not required. LogKow is also below 4.5, and so fentanyl is not considered to be a PBT substance. Therefore fentanyl is not expected to pose a risk to the environment. The ERA is acceptable.

2.3.6. Discussion on non-clinical aspects

The non-clinical development programme for IONSYS consists of a range of study reports and literature, mainly to compile a complete non-clinical safety profile of fentanyl. Fentanyl (mostly as fentanyl base or as fentanyl citrate) has previously been extensively tested in non-clinical studies and many of these were conducted in the 1960’s and 1970’s. These studies were all presented at the time of approval of the original IONSYS application, and included a selection of transdermal animal studies (safety pharmacology and topical pharmacokinetics), a 5-week repeat-dose study by continuous IV infusion in the rat, preceded by a dose range-finding study; a package of reproduction toxicity studies by continuous IV infusion; and an additional genotoxicity study. A detailed package of local tolerance and contact hypersensitivity studies on ETS system has also been supplied.

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Many of the conducted non-clinical studies used the ETS fentanyl formulation; however the formulation of fentanyl used in the SSEC product is unchanged and so the only new non-clinical data provided to support this application are two new toxicology studies and one carcinogenicity study that were on-going at time of the original MAA submission.

The applicant was requested to discuss the potential risk deriving from accumulation of fentanyl in subcutaneous fat tissue following transdermal administration. Based on the pharmacokinetic and toxicological data available for IONSYS, the applicant was asked to provide a scientific justification for the time period recommended to elapse before resumption of breast-feeding following removal of the medicinal product. Further to the review of the applicant position, the CHMP considered that the potential risk deriving from accumulation of fentanyl in subcutaneous fat tissue following transdermal administration had been properly discussed and that this risk was mitigated due to its rapid migration through skin to the systemic circulation, resulting also in a shorter time period recommended to elapse before resumption of breast-feeding following removal of the medicinal product.

During the review of the application, the CHMP considered that levels of the minor metabolite, para hydroxy fentanyl metabolite following clinical exposure had not been highlighted and thereby requested the applicant to further review this point, focusing on the potential consequences for clinical safety from the use of the IONSYS product. Having evaluated the responses provided by the applicant, the CHMP considered the levels of the minor active metabolite, para hydroxy fentanyl metabolite following clinical exposure to be negligible and predominantly seen in animal species and not for humans.

2.3.7. Conclusion on the non-clinical aspects

The CHMP considers that there are no objections to authorisation of this medicinal product from a non-clinical perspective.

2.4. Clinical aspects

2.4.1. Introduction

GCP

The Clinical trials were performed in accordance with GCP as claimed by the applicant

The applicant has provided a statement to the effect that clinical trials conducted outside the community were carried out in accordance with the ethical standards of Directive 2001/20/EC.

Tabular overview of clinical studies

No new clinical efficacy studies have been conducted as part of this application. However, the applicant has provided results of the studies conducted as part of the original development programme conducted for the original ETS system that was approved via the centralised route in 2006, but subsequently not renewed.

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The figure below describes all of the studies conducted with all of the different systems.

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2.4.2. Pharmacokinetics

Absorption Fentanyl is highly lipid soluble, as measured by the octanol-water distribution coefficient (log p of 2.98), and has greater access to the brain and central opioid receptors than morphine (log p of 0.0). Highly lipophilic agents like fentanyl may be rapidly absorbed in neural tissues or through the nasal and buccal mucosa. Opioids in general are readily absorbed from the gastrointestinal tract and act rapidly when administered via intravenous (IV) or intramuscular (IM) injection. The bioavailability of fentanyl after oral and oral-transmucosal administration are 32% and 52%, respectively. Approximately 92% of the fentanyl dose absorbed from a passive transdermal system reaches the systemic circulation as unchanged fentanyl; therefore, fentanyl biotransformation during passive transdermal penetration appears negligible.

Bioequivalence: The application is based on showing bioequivalence between the originally licenced system and the new system that is subject to this application. As the old system was discontinued due to malfunction concerns in the electronics, which have since been addressed (please see quality assessment), it was impossible for the applicant to perform a study directly comparing the old ETS system and their new SSEC system. They have therefore attempted to bridge across between the original system and the new system by taking study C-96-009 and performing an identical study- PK2011-001. From this the applicant then compared total dose delivered. A direct comparison of the 40µg dose was then performed with the results from study C-97-001.

C-96-009: Study C-96-009 was a pilot BA study conducted during the development of the ETS product to evaluate systemic exposure at various current levels with the intended commercial hydrogel formulation containing fentanyl hydrochloride. The primary objective of this study was to estimate the amount of fentanyl absorbed by 10-minute on-demand doses from the ETS with various current settings.

The results from Study C-96-009 indicated that a current of 170 μA (n = 16) provided an arithmetic mean dose (± standard deviation [SD]) of 39.5 (± 10.9) μg (refer to CSR C-96-009). The median dose was 35.6 μg, with twice as many subjects (n = 4) having a dose absorbed value between 35 and 38 μg, inclusive, than any other dose range interval.

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C-97-001: A full scale absolute BA study, C-97-001, was performed in the US and completed in November 1997. This was a single-centre, open-label, randomised, 3-period, 3-treatment, 2-sequence crossover trial in naltrexone-blocked subjects.

PK2011-001: This was a single-centre, randomized, open-label, 3-period, 5-treatment, 6-sequence PK study in healthy adult subjects.

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Bioequivalence measure:

Distribution

Fentanyl is distributed rapidly from plasma to highly vascular tissues (heart, lung, and brain) following an IV bolus. More than 80% of the injected dose leaves plasma in less than 5 minutes and 98.6% within an hour. The large volume of distribution for fentanyl is related to its lipophilic characteristics.

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Elimination Fentanyl is metabolized primarily in the liver. It has a high extraction ratio and clearance ranges from values as low as one-third of hepatic blood flow to those equalling hepatic blood flow. In humans, the drug is metabolized mainly by N-dealkylation to norfentanyl [4-N-(N-propionyl-anilino)-piperidine] and by hydroxylation of both fentanyl and norfentanyl to hydroxypropionyl fentanyl and hydroxypropionyl norfentanyl, respectively. Fentanyl amide hydrolysis to despropionylfentanyl and alkyl hydroxylation to hydroxyfentanyl are comparatively minor pathways, and hydroxyfentanyl is subsequently N-dealkylated to hydroxynorfentanyl, another minor metabolite.

The elimination of fentanyl from the body is governed by its reuptake from storage sites and its metabolism in the liver. The serum fentanyl concentration profile is often best described by a three-compartment model. The half-life of fentanyl is approximately 4–8 hours following IV administration and renal elimination is low in humans.

Dose proportionality and time dependencies

Special populations

The effect of renal impairment on fentanyl PK is expected to be similar to that following intravenous dosing. Although it is accepted that renal impairment will have limited effect on the PK of fentanyl, Ionsys should be administered with caution to patients with moderate or severe renal impairment.

The effect of hepatic impairment on fentanyl PK is expected to be similar to that following intravenous dosing. Fentanyl is a high hepatic extraction ratio drug; detailed data on the effect of decreased blood on pharmacokinetics of fentanyl are sparse. Ionsys should be administered with caution to patients with moderate or severe hepatic impairment.

Genetic polymorphisms:

CYP3A4 and CYP3A5 genetic polymorphisms may be associated with increased exposure to fentanyl. In one study, plasma fentanyl concentrations were 1.9 fold higher in CYP3A5 *3/*3 patients than in wild type patients. During the course of the procedure, the applicant was requested to further discuss the consequences of possible genetic polymorphism and this information was included in the SmPC.

Pharmacokinetic interaction studies

In vitro: At therapeutic concentrations, ranitidine (CYP3A4 inhibitor) inhibited the disappearance of fentanyl from an in vitro microsomal preparation, indicating that it hinders microsomal drug metabolism. Feierman showed that fentanyl metabolism by rat and human microsomes was inhibited by acetaminophen (paracetamol); however, the inhibitory constant (Ki) was 20-fold greater than the typical therapeutic blood concentration of acetaminophen, making in vivo acetaminophen-fentanyl interactions unlikely.

A wide variety of drugs given at potentially therapeutic plasma drug concentrations were tested in vitro and found to have negligible, if any, effect on fentanyl binding (0.6 and 40 ng/mL) to whole plasma. However, at drug concentrations higher than 20 μg/mL, aspirin, phenylbutazone, and quinidine were reported to cause inhibition of fentanyl binding (0.6 and 40 ng/mL) to whole plasma. Aspirin and phenylbutazone inhibited binding of fentanyl to albumin, while quinidine caused inhibition of binding to lipoproteins but not to albumin. Estrogen and progesterone therapy have been shown to increase fentanyl binding. Since fentanyl has a high hepatic extraction ratio, its clearance is most sensitive to changes in hepatic blood flow and less sensitive to

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changes in intrinsic hepatic enzyme activity and protein binding. However, alterations in fentanyl protein binding may influence its volume of distribution.

In vivo: Halothane and enflurane are strong inhibitors in the rat and are shown to delay fentanyl metabolism in humans. Schuttler and Ihmsen reported that fentanyl and alfentanil both increased the volume of the central compartment and the clearance of propofol. Other investigators have shown that both fentanyl and alfentanil decrease the propofol requirements for induction of anaesthesia, possibly because of synergistic pharmacodynamic interaction between these drugs.

Since the metabolism of fentanyl is mediated by the CYP3A4 isoenzyme, co-administration of drugs that inhibit CYP3A4 activity (e.g., erythromycin, ketoconazole) may decrease clearance of fentanyl. The expected clinical results would be increased or prolonged opioid effects. Thus, patients being treated with drugs that inhibit CYP3A4 should be carefully monitored while they are receiving fentanyl so that dose adjustments may be made as administration of ritonavir and fentanyl resulted in a 67% decrease in fentanyl clearance, a 174% increase of fentanyl AUC from time zero extrapolated to infinity (AUCinf), and a doubling of fentanyl half-life that was most likely due to inhibition of CYP3A4-mediated metabolism.

The applicant was requested to provide a discussion of any potential interactions with topical medicines. The applicant proposed that concomitant use of topical medicines should be avoided, which was agreed by CHMP and an appropriate warning was included in Section 4.5 of the SmPC.

2.4.3. Pharmacodynamics

Mechanism of action

Primary and Secondary pharmacology

The pharmacodynamics of fentanyl is well known. The applicant has provided a summary of the pharmacodynamics but no additional studies. In this case this is acceptable. The data presented is summarised below.

Fentanyl acts primarily on the central nervous system to produce analgesia and sedation. Respiratory depression, changes in mood, decreased gastrointestinal motility, nausea, vomiting, and alterations of the endocrine and autonomic nervous systems may also result. Several studies have correlated fentanyl plasma concentration with analgesia (the desired effect) and respiratory depression (the most dangerous side effect). However, the intensity of the effects correlates with the drug concentration at the site of action (effect site) and not necessarily the plasma concentration. For opioids, the effect site (or biophase) is the opioid receptor in the brain and spinal cord.

2.4.4. Discussion on clinical pharmacology

Pharmacokinetics: The applicant has provided one new pharmacokinetic study that is designed to show bioequivalence to the old system. The rest of the data comes from the old system and as such confirms the pharmacodynamics of the system. The three main studies have been described above, whilst the others are listed with basic results.

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The need for the applicant to conduct a study without the direct comparison to the ETS system is understood. Availability and safety concerns means that it was impossible to conduct a study with the ETS system. Therefore the applicant’s decision to conduct a study using the new system and IV fentanyl is accepted. Study PK2011-001 was well conducted the bioavailability parameters were in line with those seen in the previous studies with the old system.

Study C-96-009 was a pilot BA study conducted during the development of the ETS product to evaluate systemic exposure at various current levels with the intended commercial hydrogel formulation containing fentanyl hydrochloride. The results from Study C-96-009 indicated that a current of 170 μA (n = 16) provided an arithmetic mean dose (± standard deviation [SD]) of 39.5 (± 10.9) μg (refer to CSR C-96-009). The median dose was 35.6 μg, with twice as many subjects (n = 4) having a dose absorbed value between 35 and 38 μg, inclusive, than any other dose range interval. Since only 16 subjects completed the 170 μA treatment, the estimate of the mean dose absorbed can be disproportionately influenced by individual values at the extremes of the distribution.

Study C-97-001 was a single-centre, open-label, randomised, 3-period, 3-treatment, 2-sequence crossover trial in naltrexone-blocked subjects designed to confirm the bioavailability of the system. The mean dose absorbed value for the ETS 170 μA (n = 35) was 68 μg following two consecutive doses at the 23rd hour of treatment. However, four subjects (#1011, 1031, 1039, 1040) had unexpectedly high fentanyl serum concentrations (> 10 ng/mL) at 1 to 4 observation time points in the reference IV treatment, resulting in reduced apparent dose absorbed values for the respective ETS treatment (even though typical AUC values were observed for the ETS treatments). The high IV concentration values (refer to CSR C-97-001; Display 7.1.2, post-text Table 3) could not be explained by the pharmacokinetics of the drug. When these four subjects are excluded, the mean dose absorbed for the two consecutive doses at 170 μA was 74.3 μg (n = 31). The median value was also 74.3 μg, with about one-third of all individual dose absorbed values falling in the 69 to 76 μg dose interval, or about 35 to 38 μg per dose. Dose absorbed values were similar across the two treatment periods in C-97-001 (i.e., no period effect).

Study PK2011-001 was a single-centre, randomized, open-label, 3-period, 5-treatment, 6-sequence PK study in healthy adult subjects. A total of 54 eligible subjects were to receive 3 fentanyl treatments, one administered via intravenous (IV) infusion and 2 administered via the Study System. Exposure (Cmax and AUC23-24), including Dose Absorbed between 23 and 25 hours, increased with increasing current. The median tmax ranged from 23.00 to 23.17 hours across the 4 Study System treatment groups, suggesting rapid absorption of fentanyl after each hourly dosing period through 23.33 hours. Mean t1/2 values ranged from 11.0 to 13.0 hours regardless of dose absorbed or route of administration. Comparisons of the ratio of the geometric least squares mean for Dose Absorbed for the test (Study PK2011-001) versus reference (Study C-97-001) 170 μA systems fell within the bounds of the CI limit interval of 80% to 125%, thereby meeting standard bioequivalence criteria.

Bioequivalence has been shown for 40µg between C-97-001 and PK2011-001. This holds true with both sets of data from C-97-001, with the subjects that had issues included or excluded. Dose normalisation across the studies also reflects this. The doses dispensed by the devices across studies are also very similar taking into account the high variability shown across the studies.

The data presented for the previous approved system in patients shows that the exposure is similar to that seen in the healthy subjects.

The data presented above shows that there are no significant differences in exposure with differing age, sex, weight or race.

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Pharmacodynamics: The pharmacodynamics of fentanyl is well known. The applicant has provided a summary of the pharmacodynamics but no additional studies. In this case this is acceptable. The system and transdermal delivery are not expected to have any effect on the pharmacodynamics of the active.

Fentanyl acts primarily on the central nervous system to produce analgesia and sedation. Respiratory depression, changes in mood, decreased gastrointestinal motility, nausea, vomiting, and alterations of the endocrine and autonomic nervous systems may also result. Several studies have correlated fentanyl plasma concentration with analgesia (the desired effect) and respiratory depression (the most dangerous side effect). However, the intensity of the effects correlates with the drug concentration at the site of action (effect site) and not necessarily the plasma concentration. For opioids, the effect site (or biophase) is the opioid receptor in the brain and spinal cord.

2.4.5. Conclusions on clinical pharmacology

Pharmacokinetics: In conclusion, the bioequivalence comparison across the studies is accepted. The equivalence between the devices is recognised and therefore bridging to the efficacy and safety data from the previously approved application and system is acceptable.

Pharmacodynamics: The applicant’s summary of the PD of fentanyl is adequate.

2.5. Clinical efficacy

2.5.1. Dose response study(ies)

2.5.2. Main studies

The following tables summarise the efficacy results from the main studies supporting the present application. These summaries should be read in conjunction with the discussion on clinical efficacy as well as the benefit risk assessment (see later sections).

Table 2. Summary of Efficacy for pivotal trials Title: The Safety and Efficacy of Electro-transport (E-TRANS®) Fentanyl for the Treatment of Postoperative Pain: A Double-blind, Single-center, Placebo controlled Trial

Study identifier C-95-016

Design Single-centre, parallel-group, double-blind Placebo-controlled

Duration of main phase: up to 24 hours after system application

Duration of Run-in phase: not applicable

Duration of Extension phase: not applicable

Hypothesis Non-inferiority no difference in dropout rate due to inadequate pain relief between the two treatments during the treatment period i.e. ≥3 to 24-hours after treatment

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Title: The Safety and Efficacy of Electro-transport (E-TRANS®) Fentanyl for the Treatment of Postoperative Pain: A Double-blind, Single-center, Placebo controlled Trial

Treatments groups

IONSYS

E-TRANS (fentanyl HCl) 40 µg up to 6 doses/h

Each dose administered over 10 min, up to 80 doses available over 24 h

N=77

Placebo E-TRANS (placebo)


N=25

Endpoints and definitions

Primary endpoint

Withdrawal ≥3 hours after treatment

Withdrawal due to inadequate pain control (ie, whose pain control was judged by the investigator's staff to be inadequate) ≥3 hours after application of study treatment.

Secondary Withdrawal any reason

Withdrawal for any reason during the 24-hour treatment period

Secondary Pain Intensity Assessed by patient using Visual Analogue scale (VAS)

Secondary Patient Global Assessment

Assessed at time of treatment removal – categorical evaluation of the method of pain control – % excellent or good

Secondary Investigator Global Assessment

Assessed at time of treatment removal – categorical evaluation of the method of pain control

Date last treatment completed

September 1997

Results and Analysis

Analysis description

Primary Analysis

Analysis population and time point description

Per protocol – patients who had completed at least 3 hours of treatment with assigned medication

Descriptive statistics and estimate variability and effect estimate per comparison

Treatment group E-TRANS

(fentanyl) 40 µg

Placebo

Number of subject (N) 77 22

Primary endpoint: Withdrawal ≥3 hours due to inadequate pain control

6 (7.8%) 9 (40.9%)

p value 0.0001

Secondary endpoint

Withdrawal any reason

9 (11.7%)

9 (40.9%)

p value 0.0017

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Title: The Safety and Efficacy of Electro-transport (E-TRANS®) Fentanyl for the Treatment of Postoperative Pain: A Double-blind, Single-center, Placebo controlled Trial

Secondary endpoint

Pain Intensity

Mean VAS

20.6 (1.93)

37.3 (5.76)

p-value 0.0006

Secondary endpoint

Patient Global Assessment of Excellent or Good

69 (89.6%) 13(59.1%)

p-value 0.0008

Secondary endpoint

Investigator Global Assessment of Excellent or Good

69 (89.6%)

13 (59.1%)

p-value 0.0008

Summary of Efficacy for trial C-2000-008 Title: The Safety and Efficacy of Electro-transport (E-TRANS~ fentanyl for the Treatment of Postoperative Pain: A Double-Blind, Multi-center, Placebo-Controlled Trial

(Protocol No. C-2000-008-02)


Design Multi-centre, parallel-group, double-blind Placebo-controlled





Treatments groups

IONSYS



N=154



N=51

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Title: The Safety and Efficacy of Electro-transport (E-TRANS~ fentanyl for the Treatment of Postoperative Pain: A Double-Blind, Multi-center, Placebo-Controlled Trial

(Protocol No. C-2000-008-02)


Primary endpoint


Withdrawal due to inadequate pain control (ie, whose pain control was judged by the investigator's staff to be inadequate) ≥3 hours after application of study treatment. The number of hours completed in the study was summarized for each treatment group for dropouts due to inadequate pain relief.

Secondary Withdrawal for any reason


Secondary Pain Intensity

Assessed by patient using Visual Analogue scale (VAS)

Secondary Patient Global Assessment

Assessed at time of treatment removal – categorical evaluation of the method of pain control, % excellent or good

Secondary Investigator Global Assessment



January 2001



Primary Analysis





(fentanyl) 40 µg

Placebo


Primary endpoint: Withdrawal ≥3 hours after treatment due to inadequate pain control

36 (25.4%)

19 (40.4%)

p value 0.0486

Secondary endpoint

Withdrawal for any reason

46 (32.4%)

25 (53.2%)

p value 0.0107

Secondary endpoint

Pain Intensity

Mean VAS

30.9 (2.39)

40.8 (4.61)

p-value 0.0474

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Title: The Safety and Efficacy of Electro-transport (E-TRANS~ fentanyl for the Treatment of Postoperative Pain: A Double-Blind, Multi-center, Placebo-Controlled Trial

(Protocol No. C-2000-008-02)

Secondary endpoint


96 (67.6%)

25 (53.2%)

p-value 0.0743

Secondary endpoint


102 (71.8%)

25 (53.2%)

p-value 0.0183

Summary of Efficacy for trial C2001 011 Title: The Safety and Efficacy of Electro-transport E-TRANS (fentanyl HCl) 40 µg for the Treatment of Post-Operative Pain: A Double-Blind, Multicentre, Placebo Controlled Trial Incorporating JCAHO Pain Management Standards

Study identifier C2001 011

Design Multi-centre, parallel-group, double-blind Placebo-controlled





Treatments groups

IONSYS



N=244



N=240


Primary endpoint


Withdrawal due to inadequate pain control (ie, whose pain control was judged by the investigator's staff to be inadequate) ≥3 hours after application of study treatment. The number of hours completed in the study was summarized for each treatment group for dropouts due to inadequate pain relief.



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Title: The Safety and Efficacy of Electro-transport E-TRANS (fentanyl HCl) 40 µg for the Treatment of Post-Operative Pain: A Double-Blind, Multicentre, Placebo Controlled Trial Incorporating JCAHO Pain Management Standards


Assessed by patient using Visual Analogue scale (VAS)

Secondary Patient Global Assessment of Excellent or Good

Assessed at time of treatment removal – categorical evaluation of the method of pain control, % excellent or good

Secondary Investigator Global Assessment of Excellent or Good



March 2002



Primary Analysis





(fentanyl) 40 µg

Placebo


Primary endpoint: Withdrawal ≥3 hours after treatment due to inadequate pain control

64 (27.2%)

116 (56.9%)

p value < 0.0001

Secondary endpoint


81 (34.5%)

128 (62.7%)

p value < 0.0001

Secondary endpoint

Pain Intensity

Mean VAS

3.4

5.3

p-value <0.0001

Secondary endpoint


179 (76.2%)

106 (52.0%)

p-value < 0.0001

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Title: The Safety and Efficacy of Electro-transport E-TRANS (fentanyl HCl) 40 µg for the Treatment of Post-Operative Pain: A Double-Blind, Multicentre, Placebo Controlled Trial Incorporating JCAHO Pain Management Standards

Secondary endpoint


176 (74.9%)

107 (52.5%)

p-value < 0.0001

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Summary of Efficacy for trial C-2000-007 Title: The Safety and Efficacy of Electrotransport (E-TRANS®) Fentanyl Compared to IV PCA Morphine for the Treatment of Postoperative Pain


Design Multicentre, randomised, stratified, open label, parallel-group

Active-controlled




Hypothesis Non-inferiority: primary efficacy analysis was the construction of a 95% confidence interval for the difference in the success rate based on the patient global assessment (24-hour patient global assessment response of good or excellent) data between the two treatment groups, E-TRANS® (fentanyl) and IV PCA morphine

Treatments groups

IONSYS



N=316

Placebo IV PCA morphine (1 mg/dose, up to 10 doses/h), each dose administered as a bolus, followed by a 5-min lockout period

N=320


Primary endpoint

Patient global assessment

The primary efficacy analysis was the construction of a 95% confidence interval for the difference in the success rate based on the patient global assessment (24-hour patient global assessment response of good or excellent) data between the two treatment groups, E-TRANS® (fentanyl) and IV PCA morphine.

Secondary Withdrawal ≥3 hours after treatment due to inadequate pain control

Proportion of patients who were withdrawn from the study more than 3 hours after Hour 0 because the investigator's staff judged that the patient's pain control was inadequate.




Mean pain intensity over the 24-, 48-, and 72-hour treatment periods. Assessed by patient using Visual Analogue scale (VAS)

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Title: The Safety and Efficacy of Electrotransport (E-TRANS®) Fentanyl Compared to IV PCA Morphine for the Treatment of Postoperative Pain





Date last patient completed

11 March 2001



Primary Analysis





(fentanyl) 40 µg

IV PCA


Primary endpoint: Patient global assessment

232 (74.8%)

246 (77.8%)

Difference in Success Rate Between Two Treatments -3%

95% Cl (-9.7%, 3.7%)*

p value 0.3756

Secondary endpoint

Withdrawal ≥3 hours inadequate pain control

44 (14.2%) 30 (9.5%)

95% Cl -0.4%, 9.8%

p value 0.0686

Secondary endpoint

Pain Intensity

Mean VAS

31.9 (1.57) 30.6 (1.43)

p-value 0.5179

Secondary endpoint

Withdrawal for any reason 76 (24.5%) 76 (24.1%)

p-value 0.8920

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Title: The Safety and Efficacy of Electrotransport (E-TRANS®) Fentanyl Compared to IV PCA Morphine for the Treatment of Postoperative Pain

Secondary endpoint


249 (80.3%) 261 (82.6%)

95% CI -8.4%, 3.8%

p-value 0.4644

Notes * This was a pre-specified criterion for assessing therapeutic equivalence

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Summary of Efficacy Title Comparison of the Safety and Efficacy of Patient Controlled Analgesia Delivered by Fentanyl HCl Transdermal System Versus Morphine IV Pump for Pain Management after Primary Unilateral Total Hip Replacement

Study identifier CAPSS-319

Design Multi-centre, open-label, randomised, comparative, parallel treatment study

Active-controlled





Treatments groups

IONSYS



N=395

Placebo IV PCA morphine,1mg morphine bolus doses with a lockout period of 5 mins, up to 10 doses/h (10mg/h) to max of 240 doses/24h (240mg/24h

N=404


Primary endpoint








Mean pain intensity over the 24-, 48-, and 72-hour treatment periods. Assessed using on a verbal numerical rating scale (NRS).

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Title Comparison of the Safety and Efficacy of Patient Controlled Analgesia Delivered by Fentanyl HCl Transdermal System Versus Morphine IV Pump for Pain Management after Primary Unilateral Total Hip Replacement






April 2005



Primary Analysis





(fentanyl) 40 µg

IV PCA



326 (83.8%)

331 (83.4%)

Difference in Success Rate Between Two Treatments

0.4%

95% Cl -4.7%, 5.6%*

p value 0.8709

Secondary endpoint


41 (10.5%)

20 (5.0%)

p value 0.0039

Secondary endpoint


56 (14.4%) 50 (12.6%)

p value 0.4598

Secondary endpoint

Pain Intensity

Mean (SEM) verbal NRS score

2.9 (0.12) 2.9 (0.11)

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Title Comparison of the Safety and Efficacy of Patient Controlled Analgesia Delivered by Fentanyl HCl Transdermal System Versus Morphine IV Pump for Pain Management after Primary Unilateral Total Hip Replacement

p-value 0.9935

Secondary endpoint


339 (87.1%) 336 (84.6%)

95% CI -2.4%, 7.4%

p-value 0.3120


Summary of Efficacy for trial CAPSS-320 Title Comparison of the Safety and Efficacy of Patient Controlled Analgesia Delivered by Fentanyl HCl Transdermal System Versus Morphine IV Pump for Pain Management after Non-emergent Abdominal or Pelvic Surgery

Study identifier CAPSS-320

Design Multi-centre, open-label, randomised, comparative, parallel treatment study

Active-controlled





Treatments groups

IONSYS



N=252

Placebo IV PCA morphine,1mg morphine bolus doses with a lockout period of 5 mins, up to 10 doses/h (10mg/h) to max of 240 doses/24h (240mg/24h)

N=254

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Title Comparison of the Safety and Efficacy of Patient Controlled Analgesia Delivered by Fentanyl HCl Transdermal System Versus Morphine IV Pump for Pain Management after Non-emergent Abdominal or Pelvic Surgery


Primary endpoint








Mean pain intensity over the 24-, 48-, and 72-hour treatment periods. Assessed using on a verbal numerical rating scale (NRS).






April 2005



Primary Analysis



Descriptive statistics and estimate variability

and effect estimate per comparison


(fentanyl) 40 µg

IV PCA



214 (85.6%)

212 (84.5%)

Treatment Difference 1.1%

95% Cl -5.1%, 7.4%*

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Title Comparison of the Safety and Efficacy of Patient Controlled Analgesia Delivered by Fentanyl HCl Transdermal System Versus Morphine IV Pump for Pain Management after Non-emergent Abdominal or Pelvic Surgery

p value 0.7211

Secondary endpoint


22 (8.8%)

6 (2.4%)

p value 0.0018

Secondary endpoint

Withdrawal for any reason 40 (16.0%) 27 (10.8%)

p value 0.0847

Secondary endpoint

Pain Intensity

Mean (SEM)verbal NRS score

3.0 (0.13)

2.9 (0.12)

p-value 0.9935

Secondary endpoint


223 (89.2%)

225 (89.6%)

95% CI -5.8%, 4.9%

p-value 0.8724


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Analysis performed across trials (pooled analyses and meta-analysis) None performed.

Clinical studies in special populations

In the ETS clinical development program, there was a sufficient number of patients ≥ 65 years of age to adequately assess efficacy of ETS 40 µg for postoperative pain management in the elderly. Overall, there were no meaningful differences in efficacy assessment outcomes in each of the elderly subgroups (65 to 74, 75 to 84, ≥ 85) compared to the non-elderly (< 65) in the placebo- and active-controlled studies.

Supportive studies

The applicant has examined system adhesion in Study AD2011-001 and usability studies in patients, healthcare professionals and healthy individuals in studies HF2011-002, HF2012-001 ad HF2013-001.

AD2011-001

Adequate adhesion using the SSEC was demonstrated in AD2011-001. The SSEC exhibited good adherence at the 2 application sites, upper outer arm and chest, over the 24-hour wearing period. There was no significant difference in the extent of adherence at the two application sites. A non-inferiority comparison showed that the 24-hour mean adhesion scores at either location (arm or chest) for the SSEC evaluated in the current study were non-inferior to those observed for the previously approved product, the ETS system, evaluated in adhesion study C-2006-021.

HF2011-002

In study HF2011-002, 29 of 30 patients were able to successfully self-administer a simulated treatment using the SSEC placebo system on the first attempt. The one participant who was unable to administer treatment understood how to do it, but had difficulty pressing the button on the device. The patient was successful in initiating a dose on the next attempt. All participants responded appropriately to a simulated system alert (audio and visual signals) by indicating that they would contact a nurse. Overall, patients found the system convenient and very easy to use at both application sites (arm and chest application areas). They liked the size and discreteness of the device and the ability to perform other necessary activities while wearing the device. Patients made no errors or near-misses that could lead to potential unsafe situations. Therefore, this study validated that patients were able to easily use the SSEC system safely.

HF2012-001

In study HF2012-001, no training was provided to the nurses or pharmacists. However, they had access to the Quick Guide that is provided with the SSEC system. Participants were able to assemble IONSYS usually in less than one minute. After assembling and applying the SSEC system to a mannequin, participants were able to correctly determine all operational states (ready state, dosing state, end of use) and comprehend system feedback (light, beeps, display). Though some had minor difficulty comprehending alerts, all participants were able to respond appropriately to system errors. Many participants noted that the SSEC system would become even easier to use upon increased familiarity with repeated use. All participants were able to remove the SSEC system from the simulated patient and dispose of the system properly. There were no errors or near-misses that could lead to potential unsafe situations. Overall, healthcare providers found

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the SSEC system to be convenient and very easy to use. They liked the size of the product, benefits of a prefilled and pre-programmed product, and the perceived ease of use by patients. Five HCPs perceived the fixed dose as a limitation.

HF2013-001

In study HF2013-001, the SSEC was used per the intended label. Taping the SSEC to the subject’s skin with non-allergenic tape was allowed. However, no taping was used during the study. All 30 subjects were able to initiate all 48 doses with the Study System. There were no errors or close-calls made by the subjects that could potentially lead to unsafe events. Overall, the subjects found the SSEC to be very easy to use and easy to initiate doses. Overall, the staff members thought that the system was easy to use. On average the staff members responded that the subjects had well to excellent understanding of the system and were very successful using it. Thus, the user groups were able to use the SSEC safely and effectively, without exhibiting any use errors or close calls that would result in potential harm. There is no significant residual risk from the system that requires further modifications to the system design, user interface, or the instructions for use.

2.5.3. Discussion on clinical efficacy

The efficacy studies included in this application are the same as in an earlier application from the same applicant for a similar product (with a different administration device), which was voluntarily recalled by the company in September 2008 due to observations of corrosion on the printed circuit board that could have potentially resulted in overdose due to self-initiation (i.e., doses delivered without dose initiation by the patient). The efficacy for the new SSEC system is therefore established based on the data on the ETS system, previously approved in 2006. This approach is deemed acceptable as the differences in this new submission concern only the improved administration device and as the bioequivalence between the two systems has been shown satisfactorily. Thereby the main clinical studies have been previously assessed in the context of the previous application.

The applicant has also provided a summary of the efficacy data from studies conducted post-authorisation. All studies with efficacy endpoints were terminated prematurely, and consequently, efficacy data was not generally reported. Study FEN-HYD-PAI-4012 demonstrated that patients randomised to Ionsys had a greater ability to mobilise than those randomised to morphine patient controlled analgesia (PCA). Other measures such as patient global assessment mean pain ratings at 24 and 48 hours, as well as the median time to fitness for discharge, showed a trend in favour of Ionsys.

Placebo Controlled Studies

C-95-016- The primary objective of this trial was to compare the safety and efficacy of ETS 40 μg versus ETS placebo in the management of the first 24 hours of post-operative pain. The proportion of patients who discontinued the study prematurely because of inadequate pain relief ≥ 3 hours after treatment inception (the primary endpoint) was significantly less for ETS 40 μg than the ETS placebo treatment group (7.8% versus 40.9%, respectively, p = 0.0001). In this well conducted study the 40µg ETS system was clearly superior to placebo. Fewer patients discontinued, pain relief was better and less rescue medication was required.

C-2000-008- The objective of this trial was to compare the safety and efficacy of ETS 40 μg versus ETS placebo in the management of the first 24 hours of post-operative pain. Results from this study demonstrated the superior efficacy of ETS 40 μg to placebo for patient-controlled analgesia once post-operative pain control was established. In evaluable patients, those who completed ≥ 3 hours of treatment, a

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significantly lower proportion of patients on ETS 40 μg (25.4%) discontinued due to inadequate analgesia than patients on placebo (40.4%, p = 0.049). In this well conducted study the 40µg ETS system was clearly superior to placebo. Fewer patients discontinued, pain relief was better and less rescue medication was required.

C-2011-011- The objective was to compare the safety and efficacy of ETS 40 μg with the safety and efficacy of ETS placebo for the management of the first 24 hours of post-operative pain. Results from this study demonstrated the superior efficacy of ETS 40 μg to placebo for patient-controlled analgesia once immediate post-operative pain control was established. In evaluable patients, those who completed ≥ 3 hours of treatment, evaluation of the primary endpoint showed a significantly lower proportion of patients on ETS 40 μg than on placebo (27.2% versus 56.9%), discontinued due to inadequate analgesia (p < 0.0001). In this well conducted study the 40µg ETS system was clearly superior to placebo. Fewer patients discontinued, pain relief was better and less rescue medication was required.

Active Controlled Studies

C-2000-007- The objective was to compare the safety and efficacy of ETS 40 μg treatment with IV PCA morphine treatment for the management of post-operative pain. Results from this study demonstrated the therapeutic equivalence according to the prespecified criteria, based on the primary efficacy endpoint, of ETS 40 μg to a standard IV PCA morphine regimen for patient-controlled analgesia once post-operative pain control was established. In evaluable patients, those who completed ≥ 3 hours of treatment, 74.8% using ETS 40 μg and 77.8% using the IV PCA morphine pump rated their assigned treatment as a good or excellent method of pain control after 24 hours of wear. The 95% confidence interval (CI) on the difference for the proportions was -9.7%, 3.7%. In this well conducted study the 40µg ETS system was comparable to IV morphine PCA. Discontinuation rates, pain relief and rescue medication use were all comparable.

CAPSS-319- The objective was to compare the safety and efficacy of ETS 40 μg treatment versus IV PCA morphine treatment for the management of post-operative pain in patients who had undergone primary unilateral total hip replacement. Additional objectives were to assess the safety of ETS 40 μg for pain management in this surgical population and to compare the clinical utility of the ETS 40 μg system to the IV PCA device. This study demonstrated that ETS 40 μg provided efficacy similar to IV PCA morphine in the management of post-operative pain following unilateral hip replacement surgery according to the pre-specified equivalence criteria. Equivalence between groups was demonstrated for the protocol specified primary efficacy endpoint, the 24 hour patient global assessment of method of pain control. In this well conducted study the 40µg ETS system was comparable to IV morphine PCA. Discontinuation rates and pain relief were all comparable. However, there was a small but statistically significant imbalance in the rates of discontinuation due to inadequate analgesia in favour of the active control. Patients and healthcare professionals all considered the ETS system easy to use and were more satisfied with it than IV morphine PCA.

CAPSS-320- The objective was to compare the safety and efficacy of ETS 40 μg treatment versus IV PCA morphine treatment for the management of post-operative pain in patients who had undergone abdominal or pelvic surgery. Additional objectives were to assess the safety of ETS 40 μg for pain management in this surgical population and to compare the clinical utility of the ETS 40 μg system to the IV PCA morphine pump. This study demonstrated that ETS 40 μg provided efficacy similar to IV PCA morphine in the management of post-operative pain following non-emergent abdominal or pelvic surgery. Equivalence between groups was demonstrated for the protocol specified primary efficacy endpoint, the24-hour PGA of method of pain control and for the mean pain intensity at24 hours. In this well conducted study the 40µg ETS system was comparable to IV morphine PCA. Discontinuation rates and pain relief were all comparable. However, there

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was a small but statistically significant imbalance in the rates of discontinuation due to inadequate analgesia in favour of the active control. Patients and healthcare professionals all considered the ETS system easy to use and were more satisfied with it than IV morphine PCA.

FEN-PPA-401- The objective was to evaluate the clinical use of ETS 40 μg treatment and IV PCA treatment for the management of moderate to severe post-operative pain in patients who had undergone an elective major abdominal or orthopaedic surgical procedure. Additional objectives were to assess pain control in both treatment groups, to compare the safety of ETS 40 μg versus IV PCA morphine, to explore the impact of care procedures of the ETS 40 μg system and the IV PCA morphine device, and to compare technical issues with both systems. This randomised, open-label, active-controlled trial demonstrated that as a method of pain control as assessed by PGA, ETS 40 μg was non-inferior to IV morphine PCA, administered in a fashion reflective of clinical practice. In this well conducted study the 40µg ETS system was comparable to IV morphine PCA. Discontinuation rates and pain relief were all comparable. Patients and healthcare professionals all considered the ETS system easy to use and were more satisfied with it than IV morphine PCA. Of note, mobility was much better on the ETS system when compared to a traditional PCA.

Uncontrolled Studies

C-93-023- This study was conducted in two parts. Part 1: 25 μg on-demand dosing regimen: To determine if up to six 25 μg fentanyl on-demand doses per hour for 24 hours administered by the patient provided safe and effective management of post-operative pain. Part 2: 40 μg on-demand dosing regimen: To determine if up to six 40 μg fentanyl on-demand doses per hour for 24 hours administered by the patient provided safe and effective management of post-operative pain. Pain intensity scores showed that both the 25 μg and 40 μg on-demand dosing regimens were effective in managing post-operative pain. No patient withdrew from treatment with either regimen due to inadequate pain control. However, patients who received the 25 μg regimen required larger numbers of on-demand doses and substantial supplementation with IV fentanyl to attain adequate pain control. The 40 μg regimen provided better efficacy than did the 25 μg regimen as indicated by lower pain intensity scores, a lower average number of on-demand doses delivered over the 24-hour treatment period, substantially less requirement for supplemental analgesia, a higher proportion of patients rating the quality of analgesia as good or excellent, and a higher percentage of patient and investigator global assessment ratings of good or excellent.

C-94-043- The objective of this study was to determine if the prescribed regimen of up to six 40 μg fentanyl on-demand doses per hour administered by the patient from the ETS system provides safe and effective management of post-operative pain on Days 2 and 3 after surgery. On Day 2 after surgery, investigator and patient global assessments indicated that ETS provided ‘good’ to ‘excellent’ analgesia for 97%–98% of patients. On Day 3, global assessments indicated ‘good’ to ‘excellent’ pain relief in 99%– 100% of patients.

C-95-019- The objective of this study was to evaluate the safety and clinical utility (efficacy) of ETS 40 μg for the management of post-operative pain following short-stay surgical procedures, during both the time after surgery when the patient remained in the hospital and for an additional 24-hour period after the patient was discharged from the hospital to a medically supervised setting. During the hospital stay, 94% of patients and 96% of physicians reported that ETS provided good or excellent analgesia. During the 24 hours in the medically supervised setting, 100% of patient and physician global assessments were "good" or "excellent."

Adhesion and Usability

AD2011-001

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Adequate adhesion using the SSEC was demonstrated in AD2011-001. The SSEC exhibited good adherence at the 2 application sites, upper outer arm and chest, over the 24-hour wearing period.

HF2011-002

In study HF2011-002, 29 of 30 patients were able to successfully self-administer a simulated treatment using the SSEC placebo system on the first attempt.

HF2012-001

In study HF2012-001 participants were able to assemble IONSYS usually in less than one minute. After assembling and applying the SSEC system to a mannequin, participants were able to correctly determine all operational states (ready state, dosing state, end of use) and comprehend system feedback (light, beeps, display).

HF2013-001

In study HF2013-001 all 30 subjects were able to initiate all 48 doses with the Study System. There were no errors or close-calls made by the subjects that could potentially lead to unsafe events.

2.5.4. Conclusions on the clinical efficacy

The presented studies show that the ETS system had good efficacy when compared to placebo, active comparator (Morphine IV PCA) and in the uncontrolled studies. Pain relief as judged by the patients and investigators was good, both in VAS measurements and global scales. Rescue medication use was good for the ETS system and patient satisfaction and mobilisation was generally improved. The studies show that efficacy is at least as good as morphine PCA and has better user satisfaction and mobilisation than with a traditional IV PCA.

Adequate adhesion using the SSEC was demonstrated in AD2011-001, confirming that the device should stay in place in a clinical setting. In study HF2011-002, 29 of 30 patients were able to successfully self-administer a simulated treatment using the SSEC placebo system on the first attempt, showing that patients in a representative population found the system easy to use without any safety concerns. In study HF2012-001 it was demonstrated that healthcare professionals found the device easy to assemble, apply and could interpret all of the signals from the device correctly, showing that the device can be safety administered and used by healthcare professionals. In study HF2013-001 all healthy volunteers found the system easy to understand and use, again further reassuring safe use.

Overall, the efficacy of the original ETS system has been proven by the studies presented and this was also confirmed during its approval via the centralised route in 2006. Post-authorisation studies with efficacy endpoints were terminated early and provide little additional efficacy data. The bioequivalence shown between the ETS and SSEC system allows for these studies to be used in the new application. The data shows efficacy as good as morphine IV PCA but with improvements in patient and healthcare professional acceptance, ease of use and also mobility. The SSEC studies looking at adhesion and utility confirm that the system is suitable for 24 hour application and is easily understood by patients and healthcare professionals alike.

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2.6. Clinical safety

No new clinical safety studies have been conducted as part of this application. However, the applicant provided the studies conducted as part of the original development programme conducted for the original ETS system that was approved via the centralised route in 2006, but subsequently not renewed.

Patient exposure

Over 2,800 subjects have been exposed to a 40µg system in controlled trials and over 10,000 units of patient exposure post approval were also recorded.

Since submission of the MAA for the previous ETS system, the clinical safety database has been extended by 3 additional active-controlled, multicentre studies that were conducted with the ETS (which included an additional 972 patients who used ETS 40 μg), marketed use of IONSYS, and subsequent studies of the ETSS and SSEC. This application provides a safety database more than twice the size of the original submission.

The studies in the MAA for the previous ETS system plus the 3 additional active-controlled studies comprise Group 1. This group includes 7 controlled studies, 7 uncontrolled studies, 6 stopped studies (discontinued because of technical faults and not for safety reasons), 10 pharmacokinetic studies, 5 clinical pharmacology studies, 5 wearing studies and 1 dose-finding study. A total of 3980 subjects in Group 1 were exposed to ETS systems; of these subjects, 2336 used ETS 40 μg. The key safety data described in this overview is from the pooled analysis of the 7 controlled studies as they permit comparison against incidence rates from placebo and morphine use. These studies included 1763 patients treated with ETS 40 μg. Safety results for the other studies in Group 1 were consistent with those seen in the controlled studies.

Treatment lasted up to 24 hours in the placebo-controlled studies and up to 72 hours in the active-controlled (IV morphine PCA) studies. Overall, 539 (30.6%) patients using ETS 40 μg in the controlled studies completed the allowable number of hours on study.

Adverse events The overall adverse event profile of the systems is as expected for an opioid used in post-operative pain. No untoward adverse event patterns are seen. When compared to IV morphine PCA, the adverse event profile is similar, if not better for the systems. Of particular benefit is the lower rate of adverse events that could be specifically described as opioid associated.

Serious adverse event/deaths/other significant events The serious adverse event profile is as expected for fentanyl. The events judged to be related to the study medication are of the type that would be expected with an opioid. Of note the rates are no different to that of the morphine IV PCA.

No deaths occurred with ETS/ETSS/SSEC 40 μg treatment while on study in any of the Group 1, Group 2, or Group 3 studies. As already reported in the MAA for the previous ETS system, 3 deaths occurred after study termination in patients who received ETS 40 μg treatment in a Group 1 clinical trial, all judged not related to study medication by investigators.

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Laboratory findings

Per protocol, clinical laboratory parameters were not assessed in the controlled, uncontrolled, and stopped studies in Group 1.

Scheduled laboratory assessments were performed in Group 2 (C-2004-016) and Group 3 (C-2006-036, FEN-PAI-1017) studies.

In study C-2004-016, clinical laboratory evaluations generally were within normal limits for subjects before the start of the study, and the Investigator did not consider any of the isolated instances of abnormal values to be clinically significant. No notable changes in the mean values were observed at the end of study assessment compared with baseline.

In study C-2006-036, there were no consistent treatment-related changes from baseline in the laboratory parameters. There were minor changes in ALT, alkaline phosphatase, bilirubin, blood urea nitrogen, and creatine kinase. These changes were not considered clinically significant and were not reported as AEs.

In study FEN-PAI-1017, there were no consistent treatment-related changes from baseline in the laboratory parameters. One subject (No. 9013), who had abnormal values at screening, was reported with elevated ALT (82 U/L) and AST levels (40 U/L) during Sequence 1, Period 2 (Day -1). The subject was withdrawn from the study for this reason.

The applicant has also referred to the product information of Durogesic® (transdermal fentanyl) and Sublimaze® (injectable fentanyl). No laboratory-related adverse reactions are listed for either product. Furthermore, a review of the literature did not reveal any clinical laboratory concerns.

Safety in special populations No overall differences were observed in the safety of ETS 40 μg between elderly patients (65 to 74, 75 to 84 and > 85 years) and adult patients (< 65 years) within the clinical safety database. The rate of AEs suggestive of CNS or respiratory depression appears to increase with age. At least one AE suggestive of CNS or respiratory depression was reported in 3.7 % of non-elderly patients, in 7.1 % of patients 65– 74 years, in 10.1 % of patients 75– 84 years, and in 18.8 % of patients ≥ 85 years of age. This kind of AE profile is as would be expected for this population using this kind of medicinal product. The contraindications and warnings included in the proposed SmPC are considered adequate to address the risk of respiratory depression in the elderly. Confusion is included as an uncommon adverse reaction in Section 4.8. Different dosage instructions for the elderly patients are not considered necessary.

Immunological events No significant events or pattern of events was seen.

Safety related to drug-drug interactions and other interactions

The postoperative use of potentially sedating medications and CYP3A4 inhibitors of fentanyl metabolism was common in the controlled studies. The incidences of nausea and hypoxia appear to differ in patients who used

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rescue medication compared with those who did not use rescue medication. The incidence of nausea appeared higher in the IV PCA group, lower in the ETS placebo group, and similar in the ETS 40 μg group for patients who used rescue medication compared with those who did not. Hypoxia was more frequently reported in those who used rescue medication compared with those who did not in both active treatment groups.

The CHMP requested the applicant to provide an analysis of adverse events according to concomitant use of CYP3A4 inhibitor. For the E-TRANS fentanyl group, the incidence of common AEs such as nausea and vomiting were comparable between the sub-group taking CYP3A4 inhibitors and the sub-group not taking CYP3A4 inhibitors. No additional safety signals were raised for concomitant use of CYP3A4 inhibitors. Appropriate warnings regarding concomitant use of IONSYS and potent or moderate CYP3A4 inhibitors were included in Section 4.5 of the SmPC.

A similar analysis of adverse events by potentially sedating medication was also provided. The incidence of hypoxia was marginally increased with concomitant potentially sedating medication in both the ETS and morphine treatment groups, as identified by the applicant. Of note, an increased incidence of pruritis was also associated with concomitant potentially sedating medication in the ETS and morphine groups. However this was considered to be potentially due to the treatment of pruritis with sedating antihistamines.

Discontinuation due to adverse events

Group 1 studies: Less than 5% of patients in the controlled studies discontinued treatment with ETS 40 μg because of an AE: (77/1763 [4.4%] overall). A similar proportion of patients discontinued for AEs in the IV PCA morphine (86/1313 [6.5%]) and placebo treatment groups (7/316 [2.2%]). The most frequently occurring AEs (in ≥ 5 patients) resulting in study termination were nausea (1.2%); pruritus (0.5%); and headache and confusional state (0.3% each) with ETS 40 μg, and nausea (1.7%); somnolence and pruritus (0.6% each); hypoventilation, vomiting, and dizziness (0.5% each); and hypotension (0.4%) with IV PCA morphine.

2.6.1. Discussion on clinical safety

The clinical safety studies included in the application have been conducted as part of the original development programme for the original ETS system that was approved in 2006. This approach is deemed acceptable as the differences in this new submission lie in the improved administration device and as the applicant has demonstrated bioequivalence between the original ETS system and the new SSEC system. Therefore the CHMP has considered that the safety profile as shown for the previous product with ETS system can be inferred on the new system subject of this application. From the safety database all the adverse reactions reported in clinical trials and post-marketing have been included in the Summary of Product Characteristics The overall adverse event profile of the systems is as expected for an opioid used in post-operative pain. No untoward adverse event patterns are seen. When compared to IV morphine PCA, the adverse event profile is similar, if not better for the systems. Of particular benefit is the lower rate of adverse events that could be specifically described as opioid associated.

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The serious adverse event profile is as expected for fentanyl. The events judged to be related to the study medication are of the type that would be expected with an opioid. Of note the rates are no different to that of the morphine IV PCA.

No deaths were reported whilst on any of the systems. Those that occurred after are not attributed to study medication. This judgement is accepted as the events are not specifically linked to fentanyl but either the surgery or underlying medical conditions.

No overall differences were observed in the safety of ETS 40 μg between elderly patients and adult patients within the clinical safety database. The rates of AEs suggestive of CNS or respiratory depression appear to increase with age, and are adequately covered in the proposed SmPC.

The applicant has adequately summarised the interaction with rescue medication and sedating medication. The applicant has also provided an analysis of adverse events according to concomitant use of CYP3A4 inducer or inhibitor.

Spontaneous report data provided in the J&J PSUR submissions further characterised local tolerability. No untoward pattern of events was seen in the reported data. When reviewed at CHMP, adverse events were recognised and the company added those to the SmPC. These were considered to be all local reactions to the system rather than concerning systemic events.

2.6.2. Conclusions on the clinical safety

Overall, the safety profile of Ionsys is as expected for fentanyl used in post-operative pain. The large safety database of over 3800 subjects exposed to a 40µg system, as well as the post marketing experience of over 10,000 units sold provides adequate safety information for this application.

The adverse events are related to the opioid activity of fentanyl and to the nature of the system itself in the application site events reported. Nothing untoward is seen when compared to morphine in a PCA and the events reported are similar to those seen with fentanyl in general. Considering that Ionsys is a novel PCA device and closer monitoring of this medicinal product in the initial stages of the post-marketing period is desired, the MAH shall submit the first periodic safety update report for this product within 6 months following authorisation.

Therefore the safety profile of fentanyl and the system is accepted.

2.7. Risk Management Plan

The CHMP received the following PRAC Advice on the submitted Risk Management Plan:

The PRAC considered that the risk management plan version 1.3 could be acceptable if the applicant implements the changes to the RMP as described in the PRAC endorsed PRAC Rapporteur assessment report.

The CHMP endorsed this advice without changes.

The CHMP endorsed the Risk Management Plan version 1.3 with the following content:

Safety concerns

Identified Risks: • Misuse/Abuse/Diversion/Addiction and dependence; • Medication Errors (including accidental exposure);

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• Drug Interactions • Respiratory depression; • Overdose; • Application site reactions;

Potential Risks • Device malfunction/failure including use during MRI cardioversion or

defibrillation; • Inadequate product disposal; • Off label use; • Use in patients with hearing impairment

Missing Information • Use in Pregnancy and breast-feeding; • Paediatric Use; • Use in hepatic impairment; • Use in renal impairment

Pharmacovigilance plan

Study/activity Type, title and category (1-3)

Objectives Safety concerns addressed Status (planned, started)

Date for submission of interim or final reports (planned or actual)

Prescriber Survey

Category 3

To evaluate prescriber awareness and understanding of the important identified and potential risks in the RMP

Misuse/Abuse/Diversion/ Addiction and Dependence • Medication errors (including accidental exposure) • Respiratory depression • Overdose • Device malfunction/ failure, including use during MRI, cardioversion, or defibrillation • Inadequate product disposal

18 months from EU launch

01/04/2018

Risk minimisation measures

Safety concern Routine risk minimisation measures Additional risk minimisation measures

Misuse/ Abuse/Diversion/ Addiction and Dependence

Please see Sections 4.1, 4.2, 4.4 and 6.6 of the SmPC where monitoring of Misuse/ Abuse/Diversion/ Addiction and Dependence is described to ensure that healthcare professionals understand the indication of IONSYS, the appropriate use, the abuse potential and risk of dependence, and that a patient must be properly informed of how to use the system.

Healthcare Provider Educational Programme

Medication errors (including accidental exposure)

Please see Sections 4.2, 4.4 and 4.8 of the SmPC where monitoring of Medication errors (including accidental exposure) is described to ensure that healthcare professionals understand the appropriate use of IONSYS and that a patient must be properly


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informed of how to use the system.

Drug interactions

Please see Sections 4.4 and 4.5 of the SmPC where monitoring of Drug interactions is described to ensure that healthcare professionals understand the risk of adverse events including respiratory depression with concomitant use of the following drugs:

• Potent CYP3A4 inhibitors or moderate CYP3A4 inhibitors

• Partial opioid agonists/antagonists

• MAO inhibitors within 14 days.

• Topical medicine at the application site.

None

Respiratory depression

Please see Sections 4.3 and 4.4 of the SmPC where monitoring of Respiratory depression is described to ensure that healthcare professionals understand how to minimize this risk.


Overdose Please see Sections 4.9 of the SmPC where monitoring of Overdose is described to ensure that healthcare professionals understand how to minimize and treat this risk.


Application site reactions

Please see Sections 4.8 of the SmPC where monitoring of Application site reactions is described to ensure that healthcare professionals understand this risk.

None

Use in patients with hearing impairment

Please see Sections 4.4 of the SmPC where monitoring of use in patients with hearing impairment is described to ensure that healthcare professionals understand the risk associated with use in this population.

None

Device malfunction/failure, including use during MRI, cardioversion, or defibrillation

Please see Sections 4.2 and 4.4 of the SmPC where monitoring of Device malfunction/failure, including use during MRI, cardioversion, or defibrillation is described to ensure that healthcare professionals understand how to use the system appropriately and how to recognize possible device issues.


Inadequate product disposal

Please see Sections 4.4 and 6.6 of the SmPC where monitoring of Inadequate product disposal is described to ensure that healthcare professionals understand the dangers of inappropriate handling of the IONSYS system and how to appropriately store it and dispose of it after use.


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Off-label use Please see Sections 4.1 and 4.2 of the SmPC where monitoring of Off-label use is described to ensure that healthcare profession, off labelals understand the indication and appropriate use of IONSYS.


Use in pregnancy or breast-feeding

Please see Sections 4.6 of the SmPC where monitoring of Use in pregnancy or breast-feeding is described to ensure that healthcare professionals understand the risks associated with use of IONSYS in this population.

None

Paediatric use Please see Sections 4.2 and 4.8 of the SmPC where monitoring of Paediatric use is described to ensure that healthcare professionals understand the risks associated with use of IONSYS in this population.

None

Use in patients with hepatic impairment

Please see Sections 4.2 and 4.4 of the SmPC where monitoring of Use in patients with hepatic impairment is described to ensure that healthcare professionals understand the risks associated with use of IONSYS in this population.

None

Use in patients with renal impairment

Please see Sections 4.2 and 4.4 of the SmPC where monitoring of Use in patients with renal impairment is described to ensure that healthcare professionals understand the risks associated with use of IONSYS in this population.

None

2.8. Pharmacovigilance

Pharmacovigilance system

The CHMP considered that the pharmacovigilance system summary submitted by the applicant fulfils the requirements of Article 8(3) of Directive 2001/83/EC.

2.9. Significance of paediatric studies

This MAA is intended to support the use of IONSYS in adult patients only. Planned clinical studies, as agreed with the EMA Paediatric Committee (PDCO), will evaluate safety of the SSEC to support dosing of paediatric patients. PIP no P/0111/2014.

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2.10. Product information

2.10.1. User consultation

The results of the user consultation with target patient groups on the package leaflet submitted by the applicant show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use.

Overall, for each question, at least 90% of the participants were able to locate the requested information, of which at least 90% were able to understand the information.

3. Benefit-Risk Balance

Benefits

Beneficial effects

The applicant has shown bioequivalence between the new SSEC system and old ETS system. This allows for the efficacy profile of the original ETS system to be applied to the SSEC. The data for the ETS system is comprehensive and shows efficacy in post-operative pain relief when compared to placebo and IV morphine PCA. The system has also demonstrated ease of use from both a patient and healthcare professional standpoint and mobility is improved when compared to a traditional IV morphine PCA.

Uncertainty in the knowledge about the beneficial effects.

The efficacy in the elderly, which is especially important as it would be expected to see high use in this age group was deemed not sufficiently discussed by the applicant. This was considered as resolved during the course of the procedure as a summary of data, including efficacy results from the studies that were conducted post authorisation, was provided and discussed satisfactorily by the applicant.

Risks

Unfavourable effects

The safety profile of Ionsys is as expected for fentanyl used in post-operative pain. The large safety database of over 3800 subjects exposed to a 40µg system, as well as the post marketing experience of over 10,000 units sold provides adequate safety information for this application. The applicant has demonstrated bioequivalence between the original ETS system and the new SSEC system (see pharmacokinetics section above) and therefore the safety profile from that application can be inferred on this new system.

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Uncertainty in the knowledge about the unfavourable effects

During the procedure a number of issues within the safety database were pointed out and further clarification was requested. Namely, the applicant presented the overall SAE rates tabulated and discussed the results shown in a satisfactory way. The applicant also further discussed possible lab findings in the context of fentanyl treatment and looked at the potential interactions discussed in the PK and PD sections. Therefore these uncertainties were considered as resolved.

Importance of favourable and unfavourable effects

The favourable effects are shown in this application. The efficacy is similar to the established treatment for post-operative pain- IV morphine PCA. However, patient and healthcare professionals rated acceptability and usability greater than that of the IV PCA and the Ionsys system also showed superior ratings of mobility, which is important in the recovery of the patient. The unfavourable effects, being the adverse event profile has been shown to be similar to the established treatment for post-operative pain- IV morphine PCA.

Benefit-risk balance

Discussion on the benefit-risk balance

Given that bioequivalence has been shown between the original ETS system and the SSEC system, the efficacy and safety profile of the ETS system (approved via the centralised route in 2006) can be used for the SSEC system in this application. The efficacy seen with the system is similar to IV morphine PCA but with usability and acceptance by both patients and healthcare professionals. Of note, mobility was also improved with the ETS system. The adverse event profile is similar to IV morphine PCA and no unexpected events were seen. However, considering that Ionsys is a novel PCA device and closer monitoring of this medicinal product in the initial stages of the post-marketing period is desired, the MAH shall submit the first PSUR for this product within 6 months following authorisation. In addition, educational materials for healthcare professionals are required in order to ensure the adequate use of the product and minimise the risks of medication errors (including accidental exposure), Device malfunction/failure, Product Disposal and Misuse/abuse/diversion/addiction and dependence. The healthcare provider programme also provides more detailed information about the administration device, please see the details in section additional risk minimisation measures in part 4 below.

Therefore, given the good efficacy and the potential benefit to patients of a non IV PCA system and the good adverse event profile, the benefit-risk assessment of this application is positive.

4. Recommendations

Based on the CHMP review of data on quality, safety and efficacy, the CHMP considers by consensus that the risk-benefit balance of Ionsys in the management of acute moderate to severe post-operative pain in adult patients is favourable and therefore recommends the granting of the marketing authorisation subject to the following conditions:

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Conditions or restrictions regarding supply and use

Medicinal product subject to special and restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).

Conditions and requirements of the Marketing Authorisation

• Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal.

The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation.

Conditions or restrictions with regard to the safe and effective use of the medicinal product

• Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

• At the request of the European Medicines Agency;

• Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

• Additional risk minimisation measures

Prior to launch of IONSYS in each Member State the Marketing Authorisation Holder (MAH) must agree about the content and format of the educational programme, including communication media, distribution modalities, and any other aspects of the programme, with the National Competent Authority.

The MAH shall ensure that, following discussions and agreement with the National Competent Authorities in each Member State where IONSYS is launched all healthcare professionals who are expected to prescribe, dispense or administer IONSYS are informed through an information letter on having access to / are provided with the following items:

• Summary of Product Characteristics (SmPC) and Package Leaflet

• IONSYS Instructions for Use and Disposal

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• Educational material (including prescriber checklist) for the healthcare professionals

The Healthcare provider educational Programme shall contain the following key messages:

• Information on the adequate use of the product with regards to medication errors (including accidental exposure), Device malfunction/failure, Product Disposal and Misuse/abuse/diversion/addiction and dependence.

• Information highlighting that IONSYS is a patient-controlled device to be used in a hospital setting only and that standard practices for monitoring patients using such devices should be followed by healthcare professionals.

• Information to aid healthcare professionals in selecting patients appropriate for treatment with IONSYS.

• The importance of the healthcare professional ensuring that the patient understands how to operate the IONSYS system and that only he/she can press the dosing button during use.

• The importance of reading the “IONSYS Instructions for Use and Disposal” including the troubleshooting guide and ensuring that the patient understands what to do in the event of a device failure/malfunction.

• Checklist for monitoring inadequate product disposal to ensure healthcare professionals understand the dangers of inappropriate handling and accidental exposure to the IONSYS system.

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authorised - european medicines agency€¦ · pharmacodynamics..... 30 2.4.4. discussion on...

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