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Australian public assessment report for Dolutegravir (as sodium)
Therapeutic Goods Administration
May 2014
Australian Public Assessment Report for Dolutegravir (as sodium)
Proprietary Product Name: Tivicay
Sponsor: ViiV Healthcare 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 2014This 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 Tivicay ViiV Healthcare Pty Ltd Pty Ltd PM-2012-04124-1-2Final 19 May 2014
Page 3 of 89
ContentsList of the most common abbreviations used in this AusPAR5I. Introduction to product submission9Submission details9Product background9Regulatory status10Product Information10II. Quality findings11Drug substance (active ingredient)11Drug product11Biopharmaceutics11Quality summary and conclusions12III. Nonclinical findings12Introduction12Pharmacology12Pharmacokinetics15Toxicology17Nonclinical summary and conclusions24IV. Clinical findings28Introduction28Pharmacokinetics28Pharmacodynamics33Efficacy34Safety35Clinical summary and conclusions: first round36List of questions37Second round evaluation in response to questions38Clinical summary and conclusions: second round55V. Pharmacovigilance findings56Risk management plan56VI. Overall conclusion and risk/benefit assessment63Quality63Nonclinical64Clinical64Risk management plan76Risk-benefit analysis76Outcome87Attachment 1.Product Information88Attachment 2. Extract from the Clinical Evaluation Report88
List of the most common abbreviations used in this AusPAR
Abbreviation
Meaning
3TC
lamivudine
ABC
abacavir
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ART
antiretroviral therapy
ASA
Australian Specific Annex
AST
aspartate aminotransferase
ATV
atazanavir
AUC
area under the plasma concentration-time curve
AUC0-
area under the plasma concentration-time curve from time zero to time infinity
BCRP
Breast Cancer Resistance protein
BCV
boceprevir
BID
bis in die (twice daily)
BMCs
blood mononuclear cells
Cmax
maximum plasma drug concentration
C
pre dose (trough) concentration at the end of the dosing interval
CDC
Centres for Disease Control
CI
confidence interval
CL/F
apparent clearance
CMI
Consumer Medicines Information
CNS
central nervous system
CSR
Clinical Study Report
DILI
drug induced liver injury
DRV
darunavir
DTG
dolutegravir
Emax
maximum response achievable from a drug
ECG
electrocardiogram
EFV
efavirenz
EMA
European Medicines Agency
ET
etravirine
EVG
elvitegravir
FDA
Food and Drug Administration (US)
FPV
fosamprenavir
FTC
emtricitabine
GD
gestational day
GI
gastrointestinal
GLP
Good Laboratory Practice
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IC50
inhibitory concentration 50%
IC90
inhibitory concentration 90%
ICH
International Conference on Harmonisation
IM
intramuscular
IN
integrase
INI
integrase inhibitor
IV
intravenous
LC-MS
liquid chromatography-mass spectrometry
LOEL
lowest observed effect level
LPV
lopinavir
mITT-E
Modified Intent to Treat Exposed
MRHD
maximum recommended human dose
MS
mass spectrometry
MSDF
Missing, Switch or Discontinuation = Failure
NMR
nuclear magnetic resonance
NNRTI
non nucleoside reverse transcriptase inhibitor
NOAEL
no observed adverse effect level
NOEL
no observed effect level
NRTI
nucleoside reverse transcriptase inhibitor
OMP
omeprazole
PBMCs
peripheral blood mononuclear cells
PD
postnatal day
PI
Product Information
PO
per os (oral administration)
PP
Per Protocol
PRO
protease
PSUR
Periodic Safety Update Report
QD
quaque die (once daily)
RAL
raltegravir
RBT
rifabutin
RMP
Risk Management Plan
RPV
rilpivirine
RTI
reverse transcriptase inhibitor
RTV
ritonavir
SAE
serious adverse events
SC
subcutaneous
SOC
System Organ Class
t1/2
terminal half-life
Tmax
time to reach maximum plasma concentration following drug administration
TDF
tenofovir disoproxil fumarate
TLOVR
time to loss of virologic response
TTC
threshold of toxicological concern
TVR
telaprevir
UGT
UDP-glucuronosyltransferase
V/F
apparent volume of distribution
XRPD
X-ray powder diffraction
I. Introduction to product submissionSubmission details
Type of Submission
New Chemical Entity
Decision:
Approved
Date of Decision:
17 January 2014
Active ingredient:
Dolutegravir (as sodium)
Product Name:
Tivicay
Sponsors Name and Address:
ViiV Healthcare Pty Ltd
Level 4, 436 Johnston Street
Abbotsford VIC 3067
Dose form:
Film coated tablets
Strength:
50 mg
Container:
High density polyethylene (HDPE) bottle
Pack size:
30 tablets
Approved Therapeutic use:
Tivicay is indicated for the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents in adults and children over 12 years of age and weighing 40 kg or more.
Route of administration:
Oral
Dosage:
50 mg once daily (patients infected with HIV-1 without resistance to the integrase class) or 50 mg twice daily (patients infected with HIV-1 with resistance to the integrase class)
ARTG Number
205212
Product background
This AusPAR describes a submission by the sponsor, ViiV Healthcare Pty Ltd, to register a new chemical entity, dolutegravir (DTG), with the trade name Tivicay. DTG is a 2-metal binding integrase inhibitor (INI) developed as a treatment for HIV-1 infection. DTG is a potent, low nanomolar inhibitor of both HIV integrase recombinant enzyme and of HIV replication in cell culture assays, retaining activity against major integrase resistance mutations. The proposed indication is:
For the treatment of human immunodeficienc