Therapeutic Goods Administration
January 2013Australian Public Assessment Report for Dapagliflozin propanediol monohydrate
Proprietary Product Name: Appebb, AZ Dapagliflozin, BMS Dapagliflozin, BMS/AZ Dapagliflozin, Edistride, Empliciti and Forxiga
Sponsor: Bristol-Myers Squibb Australia Pty Ltd / AstraZeneca Pty Ltd
About the Therapeutic Goods Administration (TGA)
· The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and Ageing, and is responsible for regulating medicines and medical devices.
· 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 <www.tga.gov.au.
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 2013
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 <>.
PM-2010-03812-35 Final 14 January 2013 / Page 2 of 116
Therapeutic Goods Administration
Contents
I. Introduction to product submission 4
Submission details 4
Product background 5
Regulatory status 6
Product Information 7
List of abbreviations used in this AusPAR 7
II. Quality findings 8
Drug substance (active ingredient) 8
Drug product 9
Biopharmaceutics 9
Advisory committee considerations 9
Quality summary and conclusions 10
III. Nonclinical findings 10
Introduction 10
Pharmacology 10
Pharmacokinetics 13
Toxicology 15
Nonclinical summary and conclusions 26
IV. Clinical findings 29
Introduction 29
Pharmacokinetics 29
Pharmacodynamics 40
Efficacy 43
Safety 53
List of questions 66
(1) Clinical summary and conclusions 67
Second round clinical evaluation 70
(2) Clinical summary and conclusions 79
V. Pharmacovigilance findings 80
Risk management plan 80
VI. Overall conclusion and risk/benefit assessment 86
Quality 86
Nonclinical 87
Clinical 89
Risk management plan 101
Risk-benefit analysis 101
Outcome 114
Attachment 1. Product Information 115
I. Introduction to product submission
Submission details
Type of Submission / New Chemical EntityDecision: / Approved
Date of Decision: / 5 October 2012
Active ingredient(s): / Dapagliflozin propanediol monohydrate
Product Name(s): / Appebb, AZ Dapagliflozin, BMS Dapagliflozin, BMS/AZ Dapagliflozin, Edistride, Empliciti and Forxiga
Sponsor’s Name / Bristol-Myers Squibb Australia Pty Ltd
4 Nexus Court, Mulgrave ,VIC 3170
Dose form(s): / Film-coated tablets
Strength(s): / 10 mg
Container(s): / Aluminium (Al)/Al blister
Pack size(s): / 7 and 28 tablets
Approved Therapeutic use: / “Monotherapy
Appebb, az, dapagliflozin, bms, edistride, empliciti, forxiga is indicated as an adjunct to diet and exercise in patients with type 2 diabetes mellitus for whom metformin is otherwise indicated but was not tolerated.
Initial combination
Appebb, az, dapagliflozin, bms, edistride, empliciti, forxiga is indicated for use as initial combination therapy with metformin, as an adjunct to diet and exercise, to improve glycemic control in patients with type 2 diabetes mellitus when diet and exercise have failed to provide adequate glycemic control and there are poor prospects for response to metformin monotherapy (for example, high initial HbA1c levels).
Add-on combination
Appebb, az, dapagliflozin, bms, edistride, empliciti, forxiga is indicated in patients with type 2 diabetes mellitus to improve glycemic control:
· in combination with metformin, when metformin alone with diet and exercise does not provide adequate glycemic control;
· in combination with a sulfonylurea (SU), when a SU alone with diet and exercise does not provide adequate glycemic control;
· in combination with insulin (alone or with one or both of metformin or a sulfonylurea [SU]) when the existing therapy, along with diet and exercise, does not provide adequate glycemic control.”
Route(s) of administration: / Oral
Dosage: / Abridged:
The recommended dose of Forxiga is 10 mg taken once daily at any time of the day regardless of meals.
Appebb, az, dapagliflozin, bms, edistride, empliciti, forxiga should not be used in patients with moderate to severe renal impairment (eGFR<60 mL/min/1.73m2 by MDRD or CrCl <60 mL/min by Cockcroft –Gault)
No dosage adjustment for Forxiga is necessary for patients with mild or moderate hepatic impairment. Forxiga should not be used in patients with severe hepatic impairment.
ARTG Number (s) / 180139, 180146, 180141, 180149, 180150, 180152 and 180147
Product background
This AusPAR describes the application by Bristol-Myers Squibb to register a new chemical entity, dapagliflozin, for use in the treatment of diabetes.
Dapagliflozin is the first of a new class of drugs. It is a selective and reversible inhibitor of the sodium-glucose co-transporter 2 (SGLT2), which is selectively expressed in the kidney. SGLT2 is the major transporter for glucose reabsorption in the kidney. The inhibition of renal glucose reabsorption results in glucose excretion in the urine, producing a feature of poorly controlled diabetes mellitus, glycosuria.
Dapagliflozin shares some of the biological properties of phlorizin, a plant flavonoid originally isolated from the bark of the apple tree by French chemists in the 19th century.[1] Phlorizin inhibits sodium-dependent glucose co transporter type 1 (SGLT1), which is primarily responsible for intestinal glucose absorption as well as SGLT2.
The development of dapagliflozin as a functional analogue of phlorizin whose action is specific to the renal tubular variant of SGLT thus has support in concept as a novel therapy independent of insulin action. A potential benefit of this approach may be freedom from some of the disadvantages of those diabetes therapies which increase the secretion or enhance the action of insulin, such as hypoglycaemia and weight gain.
The sponsor has proposed the following indications:
“Monotherapy
Indicated as an adjunct to diet and exercise in patients for whom metformin is inappropriate due to contraindications or intolerance.”
Add-on combination
Initial combination
Indicated for use as initial combination therapy with metformin, as an adjunct to diet and exercise, to improve glycemic control in patients with Type 2 diabetes mellitus when dual dapagliflozin and metformin therapy is appropriate.
Add-on combination:
Indicated in patients with Type 2 diabetes mellitus to improve glycemic control in combination with metformin, a thiazolidinedione (TZD), a sulfonylurea (SU), or insulin (alone or with up to two oral anti-diabetic medications) when the existing therapy, along with diet and exercise, does not provide adequate glycemic control.
The proposed dose is 10 mg once daily.
Regulatory status
The following table provides a list of major countries in which a similar application has been submitted and/or approved and the status of these applications.
Table 1. International regulatory status
Submission and approval status Country / Submission date / Status / Comment /European Union / December 2010 / Under evaluation / CHMP opinion expected 19 April 2012
United States / December 2010 / Under evaluation / Complete Response Letter received January 2012
Canada / January 2011 / Under evaluation / Notice of Noncompliance obtained in January with response due in April 2012
Switzerland / February 2011 / Under evaluation / Responded to first round of questions in October 2011
Brazil / February 2011 / Not approved / File rejected in October 2011, resubmission being discussed with HA
Chile / March 2011 / Under evaluation / No significant comments to date
South Africa / March 2011 / Under evaluation / No significant comments to date
New Zealand / May 2011 / Under evaluation / Questions received in November 2011, responses in progress and due March 2012
Ukraine / May 2011 / Under evaluation` / No significant comments to date
Russia / June 2011 / Under evaluation / No significant comments to date
Mexico / October 2011 / Under evaluation / No significant comments to date
CHMP=Committee for Medicinal Products for Human Use
Product Information
The approved product information (PI) current at the time this AusPAR was prepared can be found as Attachment 1.
List of abbreviations used in this AusPAR
AE adverse event
AGI alpha glucosidase inhibitor
ANCOVA analysis of covariance
BMI body mass index
BMS Bristol-Myers Squibb
CI confidence interval
CrCl creatinine clearance
CYP450 cytochrome P-450 enzyme system
CV coefficient of variation
DEXA dual energy x-ray absorptiometry
DPP dipeptidyl peptidase
eGFR estimated glomerular filtration rate
EMEA European Medicines Evaluation Agency
FPG fasting plasma glucose
GFR glomerular filtration rate
HCTZ hydrochlorothiazide
IVRS interactive voice response system
LLOQ lower limit of quantification
LOCF last observation carried forward
LC-MS-MS liquid chromatography with tandem mass spectrometry
MA marked abnormality
MRI magnetic resonance imaging
MRS magnetic resonance spectroscopy
NCI National Cancer Institute
PPK population pharmacokinetics
PTH parathyroid hormone
SAE severe adverse event
SD standard deviation
SGLT sodium-glucose co transporter
SEER Surveillance, Epidemiology and End Results (NCI program)
SOC system organ class
SU sulphonylurea
Tm tubular maximum for reabsorption
TZD thiazolidinedione
ULN upper limit of normal
ULOQ upper limit of quantification
UGT uridine diphosphate glucuronosyltransferase
II. Quality findings
Drug substance (active ingredient)
Dapagliflozin is a synthetic aryl glycoside. It has multiple chiral centres but the drug is a single enantiomer. Epimerisation is unlikely.
Figure 1. Chemical structure of dapagliflozin
dapagliflozin (propylene glycol, monohydrate solvate)
The structure is not closely related to that of other antidiabetic drugs; it perhaps bears some similarity to miglitol (Figure 2).
Figure 2. Chemical structure of miglitol.
The drug substance used in tablet manufacture is the 1,2-propanediol, monohydrate solvate of dapagliflozin (1,2-propanediol is also known as propylene glycol).
The drug substance is crystalline. Dapagliflozin aqueous solubility is relatively high and independent of pH.
Drug product
The proposed 5 mg and 10 mg (as dapagliflozin) tablets are, immediate release, film coated tablets with conventional formulations. Both strengths are yellow; they are distinguished by size, shape (5 mg round; 10 mg diamond) and tablet markings (‘5’ and ‘1427’; vs ‘10’ and ‘1428’). Neither is scored.
Some clinical trials also used 2.5 mg tablets.
The Phase III clinical trial formulation differed from the proposed formulation but no impact on bioavailability is expected.
The tablets are packed in aluminium/aluminium blisters in 7 or 28 tablet packs. Supportive dissolution and disintegration data are available from the proposed manufacturing sites. The proposal was considered acceptable.
Levels of impurities in dapagliflozin tablet batches are low although the proposed limits are lax. Limited on-going related substance testing will be done via an annual program testing stability of a batch. The approach was considered acceptable.
Tablet stability data otherwise support the proposed shelf life of 24 months when stored below 30°C.
Biopharmaceutics
Three bioavailability studies were reviewed.
Study MB102059 measured absolute bioavailability. This used a radioactive carbon (14C) labelled dapagliflozin intravenous (IV) dose given almost simultaneously with an oral 10 mg tablet dose. The mean absolute bioavailability was 78%.
Study MB102019 was the definitive food effect study (10 mg tablet). In 14 healthy male and female subjects, a high fat meal decreased peak plasma concentration (Cmax) of dapagliflozin and its 3-O-glucuronide metabolite by 31% and 43%, respectively (and delayed Tmax by about 1 h) but did not significantly alter the extent of absorption.
Studies MB102062 and MB 102090 investigated the bioequivalence of heat-stressed tablets and showed equivalence.
An acceptable justification has been provided in relation to the absence of bioequivalence data for the 5 mg strength.
Advisory committee considerations
Pharmaceutical Subcommittee (PSC) of the Advisory Committee on Prescription Medicines (ACPM)
This application was considered at the 140th meeting of the PSC:
· The use of a tablet disintegration test in place of a tablet dissolution test was considered acceptable if supported by sufficient batch data. Sufficient data have been provided.
· The sponsor’s proposal of not testing related substances at release was considered to require undertakings about future confirmatory testing. This is now considered acceptable.
· If the drug product is manufactured at more than one manufacturing site, the PSC stated that process validation, batch analysis and stability data should be provided on the drug product manufactured at each of these sites. Adequate data and assurances have been provided with regard to batch data and validation data. Given that the registration of a new tablet manufacturing site after registration does not need submission of stability data, this will not be pursued. (Stability data are routinely generated for all sites as part of Good Manufacturing Practice.) Thus, the evaluator recommended registration of both sites.