Introduction to Dissertation Phase-1

Preparation of draft ANDA Dossier of Donepezil

Hydrochloride; Memantine Hydrochloride extended
release capsule as per USFDA

Prepared By: Guided By:

Pooja Prajapati Ms. Asmatbanu M. Pathan
En. No.: 212880827003 Assistant professor
M. Pharm- SEM- III Pharmaceutical Regulatory Affairs
Pharmaceutical Regulatory Affairs GTU-Graduate School of
GTU-Graduate School of Pharmacy
Pharmacy
Date: 07/01/2023
 Content
1 Introduction

2 Literature Review

3 Patent Information

CONTENT 4 Aim, Objective & Rationale

5 Module 1

6 Plan of Work

77 Reference 2
 Alzheimer’s Disease(AD) [1-3]
SYMPTOMS
DEMENTIA is a loss of brain Healthy • Regular problems with
function that affects reasoning, Cortex
memory
memory, & behavior, & which • Issues with thinking &
interferes with everyday life.
Enlarged reasoning, planning & /or
Ventricle performing familiar tasks
AD is the most common cause Healthy
• Problems
Ventricle making
of dementia among older adults.
judgements & decisions
AD is an irreversible, • Depression & loss of
progressive brain disorder that Shrunken enthusiasm
Cortex • Mood swings
cause parts of the brain to
shrink when brain cells die. Figure 1:Comparison of healthy and AD patient brain [2]
RISK FACTORS
• Aging
• Genetics
1 Cholinergic Hypothesis
• Family
PATHOPHYSIOLOGY 2 Amyloid Plaques History
3 Tau Tangles 3 • Other

Figure 2:Neuronal damage [2] 3

 Pathophysiology [3-5]
Cholinergic Hypothesis Amyloid Plaques

Figure 3:Cholinergic Hypothesis [3] Figure 4:Amyloid Plaques [4]

Tau Tangles

Figure 5:Tau Tangles [5] 4

 Prevalence of Alzheimer’s Disease [6]
•By 2025, the number of people
age 65 and older with
Alzheimer's dementia is
projected to reach 7.1 million —
almost a 22% increase from the
5.8 million age 65 and older
affected in 2020.

•By 2050, the number of people

age 65 and older with
Alzheimer's dementia is
projected to reach 13.8 million.

Figure 6: Alzheimer's dementia prevalence in the U.S. population

(total and by age group), projected from 2010 to 2050.

5
Food and Drug Administration and FDA’s Function [7]

Protecting the public health

Regulating tobacco products

Assuring cosmetics and dietary supplements are

safe and properly labelled

Protecting the public from electronic product

radiation

Advancing public health by helping to speed

product innovations

6
 Abbreviated New Drug Application (ANDA) [8,9]
A generic medicine that is comparable to a brand-name or reference-listed drug product in dose
form, strength, quality, and intended application must submit an ANDA.

The following regulations directly apply to the ANDA process:

21 CFR Part 314: Applications for FDA approval to

Market a New Drug

21 CFR Part 320: Bioavailability and Bioequivalence

Requirements

7
ANDA Regulatory Review Process of the USFDA [9]

Bioequivalence Review
Acceptable? YES Preapproval YES
Inspection ANDA
Chemistry/Micro/Labeling Acceptable?
Review Acceptable?
NO
NO

Bioequivalence Deficiency Letter/ Approval deferred pending

Not Approvable Letter satisfactory results

Figure 7: ANDA Regulatory Review Process of the USFDA 8

 Common Technical Document (CTD) [10]
• The CTD is a set of
specifications for the
application dossier for the
registration of Medicines.
• eCTD is the electronic transfer
of information to RAs and
submitted in PDF documents.

Figure 8: CTD Triangle 9

 Literature Review
Table 1: Literature Review
USFDA Guidance for industry This guidance is to help applicants create ANDAs that can be submitted
(June 2019) ANDA Submissions to the FDA.
— Content and Format
Generics Revision 1 [11]
21 CFR 314: Applications for This guidance provides details on the ANDA Approval process, and the
FDA Approval to Market a New documentation needs for the submission. (a) facilitate the approval of
Drug [12] pharmaceuticals that have been proven to be safe and effective; and (b)
Ensure that drugs that haven't been proven to be safe and effective are
rejected.
ICH M4 Guideline for CTD This guidance provides a standard format, to prepare CTD for
Modules [13] applications that will be presented to RAs. This CTD is divided into 4
separate sections, M4 Organise, M4Q, M4S, and M4E. CTD is
organized into 5 modules, modules 1 to 5. Module 1 is regional specific
and Module 2,3,4 and 5 are intended to be common for all regions.
Chapter 14 Alzheimer’s Disease This chapter provides the data about pathophysiology and other
[14]
information of Alzheimer Disease.

10

Information about Donepezil
and Memantine Hydrochloride
extended-release capsules
10:28mg [15,16]
A Research article: Memantine
in patients with Alzheimer’s
disease receiving donepezil:
new analyses of efficacy and
safety for combination therapy
[17]
Literature Review
Table 1: Literature Review
This page is available on the official USFDA website in their archive
documents of donepezil and memantine hydrochloride. This section
contains summary, medical, chemistry, pharmacology, statistical, clinical
pharmacology biopharmaceutics, and other information about the drug.
When memantine & cholinesterase inhibitors both use together offer
additional benefits. Combination therapy results in markedly lower rates
of clinical deterioration, acceptable safety and tolerability, and effect sizes
that are both clinically and statistically significant

A Review article: Memantine Patients with moderate to severe AD can benefit from the effective and
ER/Donepezil: A Review in well-tolerated combination medication of memantine ER & donepezil.
Alzheimer’s Disease [18] When compared to coadministration of the separate drugs, the fixed-dose
combination may be more convenient.
A Review article: It provides details on AD's causes & therapies. Treatment options include
Comprehensive Review on cholinesterase enzyme inhibitors like galantamine, donepezil, and
Alzheimer’s Disease: Causes rivastigmine, & NMDA antagonists like memantine, which enhance
and Treatment [3] cognition and alertness but do not stop the course of the disease. It also
includes future therapies and other medicines. 11
 Drug Profile: Reference listed drug(RLD) [19-21]
Approval Date: Dec 23, 2014 28mg Memantine
Application Number: N206439 Hydrochloride ER & 10mg
Namzaric®
Capsule Donepezil Hydrochloride

Figure 10:Namzaric 28mg Memantine

Hydrochloride /10mg Donepezil
Figure 9: RLD product label [20] Hydrochloride per capsule [21]

ALLERGAN SALES
LLC 12
 Drug Profile [22,23]
Table 2: Physicochemical properties

Title Donepezil Hydrochloride Memantine Hydrochloride

Name Donepezil Hydrochloride Memantine Hydrochloride
Chemical Structure

Chemical Formula C24H29NO3  HCL

C12H21N  HCL
International Union of 2-[(1-benzylpiperidin-4-yl)methyl]-5,6- 3,5-dimethyladamantan-1-
Pure and Applied dimethoxy-2,3-dihydroinden-1- amine;hydrochloride
Chemistry (IUPAC) one;hydrochloride
Name
Molecular Weight 416 215.76
Chemical Abstract 120011-70-3 19982-08-2
Service (CAS) number
13
 Drug Profile [24-26]
Table 3: Pharmacological Properties
Title Donepezil Hydrochloride Memantine Hydrochloride
Pharmacological Acetylcholinesterase inhibitor N-methyl-D-aspartate(NMDA) receptor
Classification antagonist
Dosage 10mg 28mg
Administration Oral Oral
Mechanism of
Action

Figure 10: MOA of donepezil HCl [24] Figure 11: MOA of Memantine HCl [25]
Side Effects • Slow heartbeat • Difficulty passing urine
• More stomach acid • Seizures
• Nausea and vomiting • Worsening of lung problems
14
 Drug Profile [15]
Table 4: Biopharmaceutical Properties

Title Donepezil Hydrochloride Memantine Hydrochloride

Absorption The rate and extent of absorption of donepezil Peak plasma concentrations are
hydrochloride are not influenced by food. Donepezil is achieved about 18 hours after
absorbed with a relative oral bioavailability of 100% administration with food versus
and reaches peak plasma concentrations in 3 to 4 hours. approximately 25 hours after
administration on an empty stomach.

Distribution After Multiple dose administration, donepezil The mean volume of distribution of
accumulates in plasma by 4-7 fold, and steady state is memantine is 9-11 L/kg and the
reached within 15 days. Donepezil is approximately plasma protein binding is low (45%).
96% bound to human plasma proteins.

Metabolism Donepezil is metabolized by CYP 450 isoenzymes 2D6 Memantine undergoes partial hepatic
and 3A4 metabolism.

Excretion Elimination half-life is about 70 hours. Elimination half-life is about 60-80

hours.

15
 Patent Information [27-29]
Table 5: Patent Information
Patent
Patent no. Patent Holder Filing Date Expiration
Patent Title Date

US8598233B2 Method for Administering an NMDA Allergan Sales 28/01/2013 22/11/2025

LLC
Receptor Antagonist to a Subject

US8338485B2 Composition for Administering an Allergan Sales 28/06/2012 22/11/2025

LLC
NMDA Receptor

US8039009B2 Modified Release Formulations of Allergan Sales 16/06/2005 24/03/2029

LLC
Memantine Oral Dosage Forms

16
 Aim and Objective
Aim
Preparation of draft ANDA Dossier of Donepezil Hydrochloride; Memantine
Hydrochloride extended release capsule as per USFDA.

Objective

1
To study the regulatory requirements of Generic
pharmaceutical product as per USFDA.

To study the overview of Alzheimer Disease and its

2 Donepezil Hydrochloride, Memantine Hydrochloride

extended release capsule for treatment.

3
To study the preparation of dossier as per CTD and eCTD
format.

To prepare draft dossier for the registration of Donepezil

4 Hydrochloride, Memantine Hydrochloride (10mg:28mg)

extended release capsule as per USFDA.
17
 Rationale
•Neurodegenerative disease Donepezil + Memantine Better Results
•Most common type of dementia
•6th leading cause of death in the US
Than monotherapy in terms of
Estimated cost of treatment cognition, overall evaluation
AD present in Americans
• In 2010 ranged from $159 and daily activities.
aged 65 or older
• 5.8 million in 2020 to $215 billion.
• By 2040, these expenses
• By 2060, is expected to
are anticipated to increase Only combination drug in the USA,
nearly triple to
to between $379 & more under the brand name of NAMZARIC
14million
than $500 billion annually
Treatments: Improve • No generic version available
No cure • Patent Expire in 2025
some symptoms

Generic version of NAMZARIC in the

Cholinesterase Inhibitors (ChEIs) N-methyl-D-aspartate US market- reduces cost of the drug &
• Rivastigmine (NMDA) antagonists will be helpful for the patients.
• Galantamine • Memantine
• Donepezil
18
 Module 1: Administrative and Prescribing
Information
1.3 Administrative Information
1.4 Statement of Right References

1.2 Cover Letter 1.12

Request for Comme
nts & Advice

1.1 Form FDA 356h 1.14 Final Label

19
 Plan of Work Work Done
PERIOD 2022 2023 Work to be
MONTHS Aug Sept Oct Nov Dec Jan Feb Mar April Done
Literature Review
Identification of Topic in
Consultation with Project
Supervisor.
Introduction
Aim, Objective & Rationale
Module 1
Module 3
Module 5
Module 2 & Preparation of ANDA
draft and eCTD submission of
Donepezil Hydrochloride;
Memantine Hydrochloride as per
USFDA
Upload Finalized document to e-
CTD Software
Compilation, Preparation of thesis
and submission of thesis 20
 References
1. Alzheimer’s Association, “10 Early Signs and Symptoms of Alzheimer's”, November 2022,
https://www.alz.org/alzheimers-dementia/10_signs
2. Penn Memory Center University of Pennsylvania, "Health System "Alzheimer’s disease", October 2022,
https://pennmemorycenter.org/education-and-support-resources/understanding-my-diagnosis/ed-alzheimers-disea
se/
3. Anwal L, “a Comprehensive Review on Alzheimer’S Disease Causes and Treatment” World J. Pharm. Pharm.
Sci. 2021,10(7),1170.
4. Uddin MS, Kabir MT, Rahman MS, Behl T, Jeandet P, Ashraf GM, et al., “Revisiting the amyloid cascade
hypothesis: From anti-aβ therapeutics to auspicious new ways for Alzheimer’s disease.” Int. J. Mol. Sci.
2020,21(16),1–33.
5. News Medical & Life Sciences, “The Role of Tau Aggregation and Alzheimer’s Disease”, December 2022,
https://www.news-medical.net/whitepaper/20200128/The-Role-of-Tau-Aggregation-and-Alzheimers-Disease.asp
x
6. Alzheimer’s Association,“2020 Alzheimer’s disease facts and figures.” Alzheimer’s Dement. 2020, 16(3), 391–
460. doi: 10.1002/alz.12068.
7. USFDA, “What does FDA do?", October 2022, https://www.fda.gov/about-fda/fda-basics/what-does-fda-do
8. USFDA, “Abbreviated New Drug Application (ANDA)”, October 2022,
Abbreviated New Drug Application (ANDA) | FDA
9. N. Rafi, S. Ds, and A. Narayanan V, “Regulatory requirements and registration procedure for generic drugs in
USA,” Indian J. Pharm. Educ. 2018, Res., vol. 52, no. 4, pp. 544–549, doi: 10.5530/ijper.52.4.63.
21
 References
10. International Council for Harmonisation (ICH), “Organisation of the Common Technical Document for the
Registration of Pharmaceuticals for Human Use M4”, October 2022, M4_R4__Guideline.pdf (ich.org)
11. USFDA, “ANDA Submissions — Content and Format Guidance for Industry”, November 2022,
https://www.fda.gov/media/128127/download
12. Code of Federal Regulation (CFR), “ Part 314: Applications for FDA Approval to Market A New Drug”,
November 2022, CFR - Code of Federal Regulations Title 21 (fda.gov)
13. ICH, “CTD”, November 2022, https://www.ich.org/page/ctd
14. Mhyre TR, Nw R, Boyd JT, Hall G, Room C, Chapter 14 Alzheimer’s Disease, Protein Aggregation and
Fibrillogenesis in Cerebral and Systemic Amyloid Disease, Springer Science Business Media Dordrecht
2012,65,389–455.
15. Namzaric abbvie, “label: Highlights of Prescribing Information”, December 2022,
https://www.rxabbvie.com/pdf/namzaric_pi.pdf
16. USFDA, “Namzaric (memantine hydrochloride extended-release/donepezil hydrochloride) Capsules”,
November 2022, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206439Orig1s000TOC.cfm
17. Atri A, Molinuevo JL, Lemming O, Wirth Y, Pulte I, Wilkinson D, “Memantine in patients with Alzheimer’s
disease receiving donepezil: New analyses of efficacy and safety for combination therapy.” Alzheimer’s Res.
Ther. 2013,5(1),1–11.
18. Greig SL, “Memantine ER/Donepezil: A Review in Alzheimer’s Disease.” CNS Drugs 2015,29(11),963–970.

22
 References
19. USFDA, “ Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations”, October
2022
https://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm?Appl_Type=N&Appl_No=206439#31
479

20. U.S. National Library of Medicines, “NAMZARIC- memantine hydrochloride and donepezil
hydrochloride capsule
NAMZARIC- memantine hydrochloride and donepezil hydrochloride kit”, November 2022,
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=90fedc32-19e5-480c-afc6-f35a5cf4b9aa
21. WebMD, “Namzaric - Uses, Side Effects, and More” December 2022, Namzaric
Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing – WebMD
22. National Library of Medicines, PubChem, “Donepezil Hydrochloride”, November, 2022
Donepezil hydrochloride | C24H30ClNO3 - PubChem (nih.gov)
23. U.S. National Library of Medicines, PubChem, “Memantine Hydrochloride”, November, 2022
https://pubchem.ncbi.nlm.nih.gov/compound/Memantine-hydrochloride
24. Moghul S, Wilkinson D, “Use of acetylcholinesterase inhibitors in Alzheimer’s disease.” Expert Rev.
Neurother. 2001,1(1),61–69.
25. DrugsDetails, “Memantine”, November 2022, https://drugsdetails.com/memantine/
26. 23
USFDA, “Center for Drug Evaluation and Research Application number: 206439Orig1s000 LABELING”,
October 2022, 206439Orig1s000Lbl.pdf (fda.gov)
 References
27. Went et al.Method for Administering an NMDA Receptor Antagonist to a Subject.United State Patent US
8598233 B2, 2013
28. Went et al.Composition for Administering an NMDA Receptor. United States Patent US 8338485 B2,
2012
29. Rastogi et al.Modified Release Formulations of Memantine Oral Dosage Forms. United State Patent US
8039009 B2, 2011

24
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