Australian public assessment for fentanyl (as citrate)

Therapeutic Goods Administration

May 2014

Australian Public Assessment Report for fentanyl (as citrate)

Proprietary Product Name: Pecfent

Sponsor: AstraZeneca Pty Ltd

About the Therapeutic Goods Administration (TGA)

The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and is responsible for regulating medicines and medical devices.

The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary.

The work of the TGA is based on applying scientific and clinical expertise to decision-making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices.

The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action.

To report a problem with a medicine or medical device, please see the information on the TGA website .

About AusPARs

An Australian Public Assessment Record (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission.

AusPARs are prepared and published by the TGA.

An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations, and extensions of indications.

An AusPAR is a static document, in that it will provide information that relates to a submission at a particular point in time.

A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA.

Copyright

Commonwealth of Australia 2014. This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to .

Therapeutic Goods Administration

AusPAR Pecfent fentanyl (as citrate) AstraZeneca PM-2013-01123-1-1Date of Finalisation 20 May 2014

Page 18 of 19

Contents

List of the most common abbreviations used in this AusPAR4

I. Introduction to product submission5

Submission details5

Product background6

Regulatory status6

Product Information6

II. Quality6

Rate and extent of absorption6

Metabolism and distribution7

Mode, route and rate of elimination7

Active entity7

Effects of gender7

Effects of genetic polymorphism7

Administrative information8

Quality summary and conclusions12

III. Nonclinical findings13

IV. Clinical findings13

V. Pharmacovigilance findings13

VI. Overall conclusion and risk/benefit assessment13

Quality13

Nonclinical14

Clinical14

Risk management plan14

Risk-benefit analysis14

Outcome17

Attachment 1.Product Information18

List of the most common abbreviations used in this AusPAR

Abbreviation

Meaning

PK

Pharmacokinetics

PD

Pharmacodynamics

PI

Product Information

CMI

Consumer Medicine Information

ARTG

Australian Register of Therapeutic Goods

BTP

Breakthrough pain

TGA

Therapeutic Goods Administration

OTFC

Oral transmucosal fentanyl citrate

Tmax

Time to maximum concentration

Cmax

Concentration maximum

CYP

Cytochrome P450

GCRP

Good clinical research practice

FCNS

Fentanyl citrate nasal spray

LOQ

Level of quantification

QC

Quality control

AUC

Area under the curve

ANOVA

Analysis of variance

CI

Confidence Interval

I. Introduction to product submissionSubmission details

Type of submission:

Major Variation

Decision:

Withdrawn

Date of decision:

3 March 2014

Active ingredient:

Fentanyl (as citrate)

Product name:

Pecfent

Sponsors name and address:

AstraZeneca Pty Ltd

PO Box 131

North Ryde NSW 1670

Dose form:

Nasal spray solution

Strength:

100 g

Container:

Metered dose pump

Pack size:

4 doses

Approved therapeutic use:

Not applicable

Route of administration:

Nasal

Dosage:

Proposed: To allow either 4 actuations (2 in each nostril) of the 100 g/ actuation strength OR the current titration step.

ARTG numbers:

185934, 185935

Product background

This AusPAR describes the application by the sponsor for an alternative dose titration regime for Pecfent.

Pecfent is a nasal spray solution containing fentanyl citrate in two dose strengths (100 g/ actuation and 400 g/ actuation).

It was registered in August 2012 for the management of breakthrough pain (BTP) in adults with cancer who are already receiving maintenance opioid therapy for chronic pain. It had not been marketed when this submission was lodged.

The maximum dose that is recommended for administration as a single dose is 800 g, administered as a 400 g actuation in each nostril. Each bottle contains 1.55 mL ensuring delivery of 8 full sprays. Bottles in their child resistant containers are supplied in cartons containing 1 or 4 bottles.

With this submission the sponsor seeks approval for an alternative dose titration regimen for the 400 g dose.

The current titration is to replace a single 200 g dose given in one nostril (2 actuations of 100) with a single 400 g dose given in one nostril. The proposed alternative titration step is for 4 actuations of 100 g given as two actuations in each nostril. This proposed dose regimen is intended to increase patient convenience. The sponsor has contended that the current titration step is less than optimal in clinical practice because it requires a patient who demonstrates a need for a dose of more than 200 g to return to their physician to receive a new prescription for the 400 g product before being able to upward-titrate.

Regulatory status

The product received initial registration on the Australian Register of Therapeutic Goods (ARTG) in August 2012.

At the time the TGA considered this application, a similar application had been submitted in the United States (Food and Drug Administration) and the European Union (European Medicines Agency) for amending the 400 g titration step in November 2012. At the time this application was considered neither of these agencies had approved the proposed alternative titration step. It has not been proposed in other countries where Pecfent is approved for marketing.

Product Information

The approved Product Information (PI) current at the time this AusPAR was prepared can be found as Attachment 1. For the most recent Product Information please refer to the TGA website at .

II. QualityRate and extent of absorption

In a pharmacokinetic study comparing PecFent (100, 200, 400 and 800 g) with oral transmucosal fentanyl citrate (OTFC), fentanyl was shown to be rapidly absorbed following single dose intranasal administration of PecFent, with median Tmax ranging from 15 to 21 minutes while Tmax for OTFC was approximately 90 minutes. The variability of the pharmacokinetics of fentanyl was considerable following treatment with both PecFent and OTFC. Relative bioavailability of fentanyl from PecFent compared to the 200 g OTFC was appropriately 120%.

Metabolism and distribution

Fentanyl is highly lipophilic and is well distributed beyond the vascular system, with a large apparent volume of distribution. Animal data have shown that, following absorption, fentanyl is rapidly distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles and fat. The plasma protein binding of fentanyl is 80 to 85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis.

The metabolic pathways following nasal administration of PecFent have not been characterised in clinical studies, but fentanyl is metabolised in the liver to norfentanyl by cytochrome CYP3A4 isoform. Norfentanyl is not pharamacologically active in animal studies. It is more than 90% eliminated by biotransformation to inactive N-deakylated and hydroxylated metabolites.

Mode, route and rate of elimination

Disposition of fentanyl following intranasal administration of PecFent has not been characterised in a mass balance study. Less than