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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