CENTER FOR DRUG EVALUATION AND

RESEARCH

APPLICATION NUMBER:

210045Orig1s000
PRODUCT QUALITY REVIEW(S)
 QUALITY ASSESSMENT

Recommendation: APPROVAL

NDA 210045
Review #01

Drug Name/Dosage Form Amlodipine and Celecoxib Tablets

Strength 2.5 mg/200 mg; 5 mg/200 mg; 10 mg/200 mg
Route of Administration Oral
Rx/OTC Dispensed Rx
Applicant Kitov Pharma Ltd
US agent, if applicable J. Paul Waymack, M.D., Sc.D.

SUBMISSION(S) DOCUMENT SUBMISSION(S) DOCUMENT

REVIEWED DATE REVIEWED DATE
Original 31-JUL-2017 Amendment 20-FEB-2018
Amendment 20-OCT-2017 Amendment 27-MAR-2018
Amendment 27-OCT-2017 Amendment 20-APR-2018
Amendment 08-DEC-2017 Amendment 20-APR-2018
Amendment 24-JAN-2018
Amendment 05-FEB-2018

Quality Review Team

DISCIPLINE PRIMARY/SECONDARY OPQ OFFICE
REVIEWER
Drug Substance Gaetan Ladouceur/Charles Jewell ONDP
Drug Product Milton Sloan/Wendy Wilson-Lee ONDP
Process Bo Jiang/Derek Smith OPF
Facility Daniel DeCiero/Derek Smith OPF
Biopharmaceutics Kaushalkumar Dave/Jing Li ONDP
Regulatory Business Grafton Adams OPRO
Process Manager
Application Technical Lead Wendy Wilson-Lee ONDP

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 QUALITY ASSESSMENT

Quality Review Data Sheet

1. RELATED/SUPPORTING DOCUMENTS

A. DMFs:
DMF Item Date Review
Type Holder Status Comments
# Referenced Completed
(b) (4) (b) (4)
II Adequate 14-SEP-2017

II Adequate 19-JAN-2018

II Adequate 09-FEB-2018

II Adequate 11-MAR-2017

B. Other Documents: IND, RLD, or sister applications

DOCUMENT APPLICATION NUMBER DESCRIPTION
IND 112830 Celecoxib and amlodipine besylate tablets
NDA 20998 Celebrex (celecoxib) Capsules
NDA 19787 Norvasc (amlodipine besylate) Tablets

2. CONSULTS

None.

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Executive Summary
I. Recommendations and Conclusion on Approvability

OPQ recommends approval of NDA 210045 for amlodipine and celecoxib tablets (2.5
mg/200 mg; 5 mg/200 mg; and 10 mg/200 mg). This action includes two product quality
post-marketing commitments (PMC 3387):

 Product Quality PMC #1: Elemental Impurities Assessment

 Product Quality PMC #2: Dissolution Method and Acceptance Criteria
Development

II. Summary of Quality Assessments

A. Product Overview

Proposed Indication(s) including Adult patients for whom treatment with both
Intended Patient Population amlodipine for hypertension and celecoxib for
osteoarthritis are appropriate
(b) (4)
Duration of Treatment

Maximum Daily Dose 10 mg amlodipine and 200 mg celecoxib

Alternative Methods of None

Administration

B. Quality Assessment Overview

Kitov Pharmaceuticals seeks approval of a fixed-dose combination, immediate-release tablet

(KIT-302) containing varying amounts of amlodipine besylate (2.5 mg, 5 mg, and 10 mg)
and 200 mg of celecoxib for the (b) (4) treatment of (b) (4) of hypertension

(amlodipine) and osteoarthritis (celecoxib). The target population for this product is adults.
The expected occurrence of pediatric patients with both hypertension and osteoarthritis is
rare.

Both celecoxib and amlodipine besylate are marketed in the United States (US) and
worldwide as individual branded and generic prescription drug products (celecoxib was
first approved in 1998 and amlodipine besylate was first approved in 1992). In addition,
amlodipine besylate is available as a combination drug product with other prescription
drugs. The reference listed drugs for this NDA are NDA 020998 for Celebrex®
(celecoxib) capsules and NDA 019787 for Norvasc ® (amlodipine besylate) tablets. The
proposed product is considered a “convenience reformulation” intended to facilitate and
improve patient compliance. This product was not granted any regulatory designations.

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 QUALITY ASSESSMENT

Key review issues for the product quality assessment included:

1. Suitability of the multiple drug substance suppliers for each active ingredient and the
impact of these different sources on final drug product quality and performance.
2. Compatibility of the active ingredients with each other in the formulation as well as the
excipients.
3. Suitability of the proposed analytical methods, including dissolution, for quality
control, especially with respect to sensitivity and selectivity for each active ingredient.
4. Suitability of the proposed manufacturing process (b) (4)

5. Suitability of the proposed control strategy for critical quality attributes (b) (4)
content uniformity, and polymorphism.
6. Qualification and control strategy (b) (4) drug product.

7. Proposal (b) (4) for microbial limits.

8. Stability of the drug product over the proposed shelf-life.

9. Suitability of the proposed container closure(s) to protect the drug product from light
(photostability studies identified potential light sensitivity of the product, proposed
labeling instructs to protect from light).
10. Adequacy of comparability protocol to support shelf-life extension post-approval.

The Applicant referenced Drug Master Files (DMFs) for the chemistry, manufacturing,
and controls information for each of the drug substance. The DMFs supporting this NDA
were found adequate based on recent reviews (see 1.A. in the Quality Data Sheet). The
Applicant provided supporting information in the NDA – namely general drug substance
properties and the regulatory specification for each drug substance.

The Applicant identified assay, content uniformity, and drug release as critical quality
attributes. The drug product critical quality attributes are justified based on the drug
product design. (b) (4)

The tablets are not film-coated. The compatibility between the

excipients and the drug substance were confirmed by compatibility studies. The drug
product manufacturing process (b) (4)
(b) (4)

(b) (4)

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 QUALITY ASSESSMENT

(b) (4)

(b) (4)

The drug product specification is adequate to ensure quality for the dosage form. The
(b) (4)
proposal for microbial limits was deemed acceptable. (b) (4)

the drug substance and excipient specifications. The analytical

procedures that are applied for the immediate release (IR) solid oral dosage forms are
appropriate for the intended use. The reference standards are all USP-grade and
acceptable. The Applicant did not include the elemental impurities risk assessment for
the drug product. Agreement to accept the risk assessment as a post-marketing
commitment was reached by the Agency and the Applicant during review (Product
Quality PMC 3387).

The dissolution method [USP Apparatus 2 (paddle) at 75 rpm; 900 ml of pH 6.8

phosphate buffer with 0.5% sodium lauryl sulfate at 37.0 ± 0.5°C] currently proposed for
the proposed fixed-dose combination (FDC) product, Amlodipine and Celecoxib Tablets,
2.5 mg/200 mg, 5 mg/200 mg, 10 mg/200 mg strengths, under the NDA 210045 is not an
optimal method for the evaluation of the dissolution characteristics of each drug
component of the proposed FDC product. Therefore, the current dissolution method has
been accepted only on an interim basis, and the Applicant has been recommended to
develop separate dissolution methods for each drug component of the combination
product as a PMC (Product Quality PMC 3387).
(b) (4)
The dissolution acceptance
(b) (4)
criteria of ‘not less than (NLT) % (Q) in 20 minutes’ for
amlodipine, and ‘NLT % (Q) in 30 minutes’ for celecoxib, revised as per FDA’s
recommendation, are acceptable on an interim basis. We recommended the Applicant
(b) (4)

new dissolution methods (to be developed as a PMC). We also recommended that the
Applicant submit the final report (b) (4)

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 QUALITY ASSESSMENT

The Applicant requested biowaiver for the middle strength (5 mg/200 mg) of the
proposed product. The proposed product does not have classical proportionality between
the strengths, due to the constant celecoxib dosage of 200 mg across the three strengths.
The Applicant adopted the approach of bracketing for the in vivo pharmacokinetic studies
and provided data to demonstrate bioequivalence of the highest and the lowest proposed
strengths compared to their corresponding listed drug products. The Applicant provided
data showing similar dissolution profiles in multi-media (b) (4)

between the highest strength (10 mg/200 mg) and the middle strength (5 mg/200 mg) of
the proposed product. Also, the Applicant provided data showing similar dissolution
across all three strengths of the proposed product in the proposed dissolution medium.
Based on the provided data/information, the biowaiver request for Amlodipine and
Celecoxib Tablets, 5 mg/200 mg, is granted.

The characterization of the degradation products and impurities information in drug

product is provided. The Applicant has indicated that there are(b) no (4)
new impurities
resulting in the new fixed combination drug product. The results of % for amlodipine
related compound A and total related substances of (b) (4) % was observed only at the three-
month time point for lots BY341015A and BY341015A. The values had returned to
more consistent levels of (b) (4) % at the 12-month time point. The Applicant
deemed the (b) (4) % results out of trend and indicated that there is insufficient data to
confirm the one time out of trend result. The Applicant agreed to review the 24 -month
stability data with consideration of tightening the related individual and total impurity
acceptance criteria if warranted.

Based on review of suitability and stability data, the primary HDPE bottle provides
adequate protection from light and no additional measures to protect the tablets from light
during commercial distribution and use are warranted based on the stability results. No
secondary packaging is proposed. The proposed container closure system is acceptable.

The Applicant proposed an expiry period of 24 months based on 12 months long-term

and six months accelerated stability data. The long-term data showed little to no
variability and conformed to the acceptance criteria. Based on this data and in
accordance with ICH Q1E, we grant a 24-month shelf life for the drug product. The
post-approval stability protocol adequately defines the storage conditions, container
closure system, quality test attributes, and time intervals for evaluation throughout the
stability program and aligns with ICH guidance.

(b) (4)

The comparability protocol for extension of drug

product expiry post-approval is approved.

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 QUALITY ASSESSMENT

The Applicant submitted a request for categorical exclusion based on 21 CFR 25.31 (a)
“No Increased Use” based on the combination drug definition of “a single product
substituting directly for two approved products that would be administered separately.”
The Applicant also included a statement regarding no extraordinary circumstances in
accordance with 21 CFR 25.15(d). The claim of categorical exclusion is acceptable.

In response to an information request, the Applicant agreed to reverse the order of the
drug substances (b) (4) in the established name (b) (4)

The Applicant proposed four drug substance manufacturing sources. The facilities were
assessed and found acceptable based on their previous inspectional history which either
covered the APIs under review or demonstrated capabilities to synthesize these APIs
through coverage of similar APIs with a lack of quality defect signals. During the drug
substance assessment, two intermediate manufacturing facilities were identified as
potentially being critical and needing an evaluation. However, after assessment of the
review and previous facility evaluations for DMF (b) (4) it was determined that
appropriate controls were in place such that no further evaluation of the facilities is
necessary.

The drug product manufacturing, packaging, and testing facilities were also assessed and
found acceptable based on their previous inspectional history demonstrating capabilities
and lack of quality defect signals for the proposed operations in this NDA. All
manufacturing, testing, and packaging facilities associated with NDA 210045 are
acceptable and in good standing.

C. Special Product Quality Labeling Recommendations (NDA only)

None.

D. Final Risk Assessment (see Attachment I)

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Wendy Digitally signed by Wendy Wilson- Lee
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 QUALITY ASSESSMENT

ATTACHMENT I: Final Risk Assessment

Final Risk Assessment - NDA 210045 Amlodipine and Celecoxib Tablets; 2.5 mg/200 mg; 5 mg/ 200 mg; 10 mg/200 mg

From Initial Risk Identification Review Assessment

Initial
Critical Quality Factors that can Final Risk Lifecycle
Risk Risk Mitigation Approach
Attribute impact the CQA Evaluation Considerations
Ranking
Assay Formulation End product testing
Container closure
Raw materials Medium Acceptable
Process/Scale/Equipment
Site
(b) (4) (b) (4)
Formulation
Container closure
Raw materials Medium Acceptable
Process/Scale/Equipment
Site
Content Formulation End product testing in compliance
Raw materials
Uniformity Process/Scale/Equipment High with USP <905> Acceptable
Site
(b) (4) (b) (4)
Formulation
Raw materials
Process/Scale/Equipment High Acceptable
Site
Microbial Limits Formulation
Container closure
Raw materials Low Acceptable
Process/Scale/Equipment
Site
Dissolution Formulation Interim dissolution method and PMC for dissolution
Raw materials
Process/Scale/Equipment High acceptance criteria implemented Acceptable method and acceptance
Site based on FDA guidance criteria development

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 QUALITY ASSESSMENT

From Initial Risk Identification Review Assessment

Initial
Critical Quality Factors that can Final Risk Lifecycle
Risk Risk Mitigation Approach
Attribute impact the CQA Evaluation Considerations
(b) (4)
Ranking
(b) (4)
Formulation
Raw materials
Process/Scale/Equipment
Low Acceptable
Site
Photostability Formulation
Container closure
Raw materials
Process/Scale/Equipment Medium Acceptable
Site

Friability Formulation
Container closure
Raw materials Low Acceptable
Process/Scale/Equipment
Site
Compatibility Formulation Compatibility studies showed no
Raw materials
Process/Scale/Equipment
Medium interaction expected for commercial Acceptable
Site formulation
Elemental Formulation Risk assessment and evaluation in PMC for elemental
Container closure Not
Impurities Raw materials
accordance with ICH Q4D Acceptable impurities assessment
Process/Scale/Equipment assessed
Site
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 QUALITY ASSESSMENT

LABELING

{For NDA only}

R Regional Information

1.14 Labeling
Highlights of Prescribing Information

-----------------------DOSAGE FORMS AND STRENGTHS--------------

Tablets (amlodipine /celecoxib): 2.5 mg/200 mg, 5 mg/200 mg, and 10mg/200 mg (3)

FULL PRESCRIBING INFORMATION: CONTENTS

3 DOSAGE FORMS AND STRENGTHS

CONSENSI (amlodipine and celecoxib) tablets, (b) (4)

(b) (4)

Reviewer’s Assessment: Adequate

Recommendation: See tracked changes

(b) (4)

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 QUALITY ASSESSMENT
(b) (4)

11 DESCRIPTION

CONSENSI (amlodipine and celecoxib) tablet is an NSAID and long-acting calcium channel
blocker for oral administration.. Each tablet contains amlodipine besylate and celecoxib 3.47
mg/200 mg, 6.93 mg/200 mg, and 13.87 mg/200 mg and is equivalent to 2.5 mg/200 mg, 5
mg/200 mg, and 10 mg/200 mg amlodipine/celecoxib respectively.

Celecoxib is chemically designated as 4-[5-(4-methylphenyl)- 3-(trifluoromethyl)-1H-

pyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole. The empirical formula
is C17 H14 F3N 3O2S, and the molecular weight is 381.38; the chemical structure is as follows:

OPQ-XOPQ-TEM-0001v03 Page 2 of 10 Effective Date: 18 Feb 2016

 QUALITY ASSESSMENT
O
H2N
S

N
N
CF 3

H3C

Celecoxib is a white to off-white powder with a pKa of 11.1 (sulfonamide moiety). Celecoxib is
hydrophobic (log P is 3.5) and is practically insoluble in aqueous media at physiological pH range.

Amlodipine besylate is chemically designated as 3-Ethyl-5-methyl (±)-2-[(2-

aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6- methyl-3,5-pyridinedicarboxylate,
monobenzenesulphonate. The molecular formula is C20 H25 CIN2 O5 •C6H6 O 3S, and the
molecular weight is 567.1; the chemical structure is as follows:

Amlodipine besylate is a white crystalline powder. It is slightly soluble in water and sparingly
soluble in ethanol.

The inactive ingredients in CONSENSI include: mannitol DC 200, croscarmellose sodium,

povidone K-30, sodium lauryl sulfate, magnesium stearate, and colloidal silicon dioxide.

Reviewer’s Assessment:

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 QUALITY ASSESSMENT

Recommendation: See tracked changes

The package insert comments were additionally added to the SharePoint document for
consolidation of label revisions for team review.

16 HOW SUPPLIE D/ST OR AG E AND HANDLING

(b) (4)

(b) (4)
CONSENSI tablets are white, (b) (4)

biconvex, (b) (4)

(b) (4)

Storage
Store at room temperature 20°C to 25°C (68°F to 77°F); [see USP Controlled Room
Temperature].
Dispense in tight, light-resistant containers (USP).

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 QUALITY ASSESSMENT

Manufacturer/distributor name listed at the end of PI, following Section #17

Distributed by

XXX
XX, XX XXXXX

Immediate Container Label

{copy/paste or refer to a representative example of a proposed container label}

(b) (4)

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(b) (4)

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(b) (4)

Reviewer’s Assessment:

1. Recommendation for Container label: Consensi® (amlodipine and celecoxib) tablets, for
oral use
a) (b) (4)

2. Relocate the equivalency statement from the principle display panel to the side panel.

3. Revise storage statement as follows:

“Store at 20°C to 25°C (68°F to 77°F)”

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 QUALITY ASSESSMENT

4. Add to 100 count immediate label-

“This package is child resistant”
“Keep the bottle tightly closed”

{copy/paste or refer to a representative example of the proposed carton label here}

Reviewer’s Assessment:

The applicant has not provided a separate copy of the proposed carton label in the NDA
submission.

5. You have provided only the immediate (primary) label, please provide sample copies of
any secondary packaging labels.

Add to 100 ct carton-

“The enclosed bottle is child resistant”

DMEPA concurs for the the salt equivalency statement should be on principal display panel.
The draft 2018 Product title guidance recommends as part of title the route of administration.

Amendment (April 25, 2018)

1. Recommendation for Container lab el: Consensi® (amlodipine and celecoxib)

a. (b) (4)

Kitov agrees with FDA’s recommendation. The draft container labels have been updated (b) (4)
®
in the principal display panel to “Consensi (amlodipine and celecoxib)”.
The following revised draft Container Labels are provided in Module 1.14.1.1:
 Draft Container Label for Low Strength 100 Count, April 2018 revision
 Draft Container Label for Low Strength 500 Count, April 2018 revision
 Draft Container Label for Mid Strength 100 Count, April 2018 revision
 Draft Container Label for Mid Strength 500 Count, April 2018 revision
 Draft Container Label for High Strength 100 Count, April 2018 revision
 Draft Container Label for High Strength 500 Count, April 2018 revision

2. Relocate the equivalency statement from the principle display panel to the side panel.

Kitov agrees with FDA’s recommendation. The draft container labels have been updated to move the
equivalency statement from the principal display panel to the right side panel. The revised draft Container
Labels are provided in Module 1.14.1.1.

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 QUALITY ASSESSMENT

3. Revise storage statement as follows:

“Store at 20°C to 25°C (68°F to 77°F)”

Kitov agrees with FDA’s recommendation. The draft container labels have been updated to revise the
storage statement regarding temperature to “Store at 20°C to 25°C (68°F to 77°F)”. The revised draft
Container Labels are provided in Module 1.14.1.1.

4. Add to 100 count immediate label- “This package is

child resistant” “Keep the b ottle tightly
closed”

Kitov agrees with FDA’s recommendation. The draft labels for the 100 count containers have been updated to
add “This package is child resistant” and “Keep the bottle tightly closed” in the left side panel. On review of the
100 count container labels, Kitov realized that a statement (b) (4)

The revised draft Container Labels are provided

in Module 1.14.1.1.

5. You have provided only the immediate (primary) label, please provide sample copies of any secondary
packaging labels.

There is no planned secondary packaging at this time, and therefore, there are no sample copies of carton
labels to provide.

(b) (4)

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(b) (4)

Reviewer’s Assessment of Response: Adequate

The applicant amendment responses are acceptable for each of the above comments. Kitov
provided copies of each the updated revised immediate label (see examples of the 100ct and
500ct for the 10mg/200 mg strength) as indicated in comment response#1 above. The immediate
labels comply with our recommendations and are acceptable. DMEPA may provide further
comment on the container closure label in a subsequent review.

List of Deficiencies:

None

Primary Labeling Reviewer Name and Date:

Milton. J. Sloan, PhD,

Sr. Chemistry Reviewer
OPQ/ONDP/Div1/Branch III
4/25/2018

Secondary Reviewer Name and Date (and Secondary Summary, as needed):

Wendy Wilson-Lee, PhD

Branch Chief
OPQ/ONDP/Div1/Branch II

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Milton Digitally signed by Milton Sloan
Sloan Date: 4/24/2018 12:04:17PM
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Wendy Digitally signed by Wendy Wilson- Lee

Wilson- Lee Date: 4/24/2018 12:07:18PM
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 BIOPHARMACEUTICS
NDA NDA 210045

Drug Product Name Amlodipine Besylate and Celecoxib Tablets

Strength 2.5 mg/200 mg, 5 mg/200 mg, 10 mg/200 mg

Route of Administration Oral

Applicant Name Kitov Pharmaceuticals, Ltd.

Review Summary
In NDA 210045, the Applicant seeks approval of Amlodipine Besylate and Celecoxib Tablets, 2.5
mg/200 mg, 5 mg/200 mg and 10 mg/200 mg, under the 505(b)(2) pathway. The proposed fixed-dose
combination (FDC) drug product is indicated to treat patient population who are administered celecoxib
capsules as well as amlodipine besylate tablets individually for the (b) (4) treatment of osteoarthritis

and hypertension, respectively.This 505(b)(2) application relies on FDA’s previous finding of safety
and effectiveness of the individual reference listed drugs (RLDs): NDA 020998 for Celebrex®
(celecoxib) capsules held by G.D. Searle, LLC and NDA 019787 for Norvasc® (amlodipine besylate)
tablets) held by Pfizer Inc. NDA 210045 is supported by bioequivalence (BE) studies and one pivotal
clinical efficacy, safety, and pharmacokinetic drug-drug interaction study.

The Biopharmaceutics review is focused on the evaluation of data supporting: 1) the proposed
dissolution method and acceptance criteria, and 2) the request of biowaiver for 5 mg/200 mg strength.
Based on the review of the provided information/data, Division of Biopharmaceutics has the following
assessment, conclusions and recommendations:

Dissolution Method: The dissolution method [USP Apparatus 2 (paddle) at 75 rpm; 900 ml of pH 6.8
phosphate buffer with 0.5% sodium lauryl sulfate at 37.0 ± 0.5°C] currently proposed for the proposed
fixed-dose combination (FDC) product, Amlodipine Besylate and Celecoxib Tablets, 2.5 mg/200 mg,
5 mg/200 mg, 10 mg/200 mg strengths, under the NDA 210045 is not an optimal method for the
evaluation of the dissolution characteristics of each drug component of the proposed FDC product.
Therefore, the current dissolution method has been accepted only on an interim basis, and the Applicant
has been recommended to develop separate dissolution methods for each drug component of the
combination product as a Post-Marketing Commitment (PMC).
(b) (4)
Dissolution Acceptance Criteria: The dissolution acceptance criteria of ‘not less than (NLT) % (Q)
(b) (4)
in 20 minutes’ for amlodipine, and ‘NLT % (Q) in 30 minutes’ for celecoxib, revised as per FDA’s
1
recommendation, are acceptable on an interim basis. The Applicant has been recommended (b) (4)

new dissolution methods (to be

developed as a PMC). The Applicant has been recommended to submit the final report (b) (4)

Biowaiver Request: The Applicant requested biowaiver for the middle strength (5 mg/200 mg) of the
proposed product. The proposed product does not have the classical proportionality between the
strengths, due to the constant celecoxib dosage of 200 mg across the three strengths. The Applicant
adopted the approach of bracketing for the in vivo pharmacokinetic studies and provided data to
demonstrate bioequivalence of the highest and the lowest proposed strengths compared to their
corresponding listed drug products. The Applicant provided data showing similar dissolution profiles
in multi- media (b) (4) between the highest strength (10 mg/200 mg) and the middle

strength (5 mg/200 mg) of the proposed product. Also, the Applicant provided data showing simila r
dissolution of the three strengths of the proposed product in the proposed dissolution medium. Based
on the provided data/information, the biowaiver request for Amlodipine Besylate and Celecoxib
Tablets, 5 mg/200 mg, is granted.

Conclusion and Recommendations: The following dissolution method and acceptance criteria are
acceptable on an interim basis for the quality control of the proposed product:

FDA’s Approved Dissolution Method and Acceptance Criteria on an interim basis

for Amlodipine Besylate and Celecoxib Tablets
2.5 mg/200 mg, 5 mg/200 mg and 10 mg/200 mg strengths
Apparatus USP Apparatus 2 (paddle)
Paddle Speed 75 rpm
Volume 900 ml
Medium pH 6.8 Phosphate Buffer with 0.5% SLS
Temperature 37.0 ± 0.5 C
(b) (4)
Acceptance Criteria Amlodipine: Not less than % (Q) at 20 minutes
(b) (4)
Celecoxib: Not less than % (Q) at 30 minutes

From the Biopharmaceutics perspective, NDA 210045 for Amlodipine Besylate and Celecoxib Tablets,
2.5 mg/200 mg, 5 mg/200 mg and 10 mg/200 mg strengths, is recommended for APPROVAL.

2
Primary Biopharmaceutics Reviewer Name and Date:

Kaushalkumar Dave, Ph.D. (04/20/2018)

Biopharmaceutics Reviewer
Division of Biopharmaceutics
Office of New Drug Products
Office of Pharmaceutical Quality

Secondary Reviewer Name and Date:

I concur with Dr. Dave’s Biopharmaceutics assessment and recommendation.

Jing Li, Ph.D. (04/26/2018)

Acting Team Lead, Biopharmaceutics Branch-1
Division of Biopharmaceutics
Office of New Drug Products
Office of Pharmaceutical Quality

3
 BIOPHARMACEUTICS ASSSESSMENT

1. LIST OF SUBMISSIONS BEING REVIEWED

Submissions Reviewed
eCTD sequence # Received date Document
0001 07/31/2017 Original NDA Submission
0010 02/05/2018 Quality/Response to Information Request
0012 03/27/2018 Multiple Submissions
0013 04/20/2018 PMR/PMC/ Quality - Response to Information
Request

2. DRUG PRODUCT

In the current Application, Kitov Pharmaceuticals, Ltd. has requested approval of Amlodipine Besylate
and Celecoxib Tablets (KIT-302, a research code name during the product development given by the
Applicant), 2.5 mg/200 mg, 5 mg/200 mg and 10 mg/200 mg, as a 505(b)(2) NDA. The proposed drug
product, Amlodipine Besylate and Celecoxib Tablets, 200 mg/2.5 mg, 200 mg/5 mg, and 200 mg/10
mg, is a fixed-dose combination (FDC) product developed as a ‘convenience reformulation’ consisting
of celecoxib, a non-steroidal anti-inflammatory drug (NSAID), and amlodipine besylate, a calcium
channel blocker antihypertensive agent, co-formulated in a single immediate release tablet. The
proposed product is developed to target the patient population who are administered celecoxib capsules
as well as amlodipine besylate tablets individually for the (b) (4) treatment of osteoarthritis and
hypertension, respectively. To establish the bioequivalence, the Applicant performed pharmacokinetic
studies with the proposed combination product, Amlodipine Besylate and Celecoxib Tablets, 2.5
mg/200 mg and 10 mg/200 mg strengths, against the listed drugs (LDs), Celebrex® (celecoxib) 200 mg
capsules and Norvasc® (amlodipine besylate) 2.5 mg, and 10 mg tablets administered together.
(b) (4)
The proposed product is intended to have an immediate release (IR) profile
(b) (4)
The
compositions of the three strengths of the proposed drug product are listed in Table 1.

4
Table 1. Composition of the proposed product

(b) (4)

2 Page(s) has been Withheld in Full as b4

(CCI/TS) immediately following this page
 (b) (4)

BCS Class Designation

In the Pharmaceutical Development Report (Module 3.2.P.2.Drug Product), the Applicant noted
amlodipine besylate as BCS Class I compound and celecoxib to be a BCS Class II compound; however
no permeability data have been provided by the Applicant to support this. No BCS Class has been
previously designated by the FDA for amlodipine besylate or celecoxib and no request for BCS
designation has been submitted under the current NDA.

4. DISSOLUTION INFORMATION
In the current submission, the applicant provided dissolution data to support the proposed dissolutio n
specifications and bio-waiver request for the intermediate strength of the proposed product, Amlodip ine
Besylate and Celecoxib Tablets; 5 mg/200 mg. Also, the Applicant used dissolution testing during the
stages of formulation and manufacturing development. The Applicant provided a dissolution method
development report within the Pharmaceutical Development Report provide in the Module 3.2.P.2.2.3.
The Applicant’s originally proposed dissolution method and acceptance criteria are as following:
Table 9. Dissolution method and acceptance criteria originally proposed by the Applicant
(b) (4)
Apparatus
Paddle Speed
Volume
Medium

Temperature
Acceptance Criteria

8 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately

following this page
 (b) (4)

Table 10. Dissolution method and acceptance criteria newly proposed by the Applicant and
accepted by the FDA on interim basis

Apparatus USP Apparatus 2 (paddle)

Paddle Speed 75 rpm
Volume 900 ml
Medium pH 6.8 Phosphate Buffer with 0.5% Sodium
Lauryl Sulfate
Temperature 37.0 ± 0.5°C

Dissolution Acceptance Criteria

(b) (b) (4)
The Applicant proposed (b)dissolution acceptance criteria of ‘NLT (4)% (Q) in minutes’ for celecoxib
(b)
and ‘NLT (4)% (Q) in (4)
minutes’ for amlodipine. Data provided in Figure 9 and 10 suggest that the
following dissolution acceptance criteria are suitable for the proposed product at paddle speed of 75
rpm:
(b)
Amlodipine: NLT (4)% (Q) at 20 minutes
Celecoxib: NLT (b) (4)% (Q) at 30 minutes

Via an IR dated 04/11/2018, the Applicant was recommended to implement these dissolutio n
acceptance criteria. Via an IR response dated 04/13/2018, the Applicant accepted the FDA
(b) (4)
recommendation and revised the dissolution acceptance criteria to ‘NLT % (Q) at 20 minutes’ for
(b) (4)
amlodipine, and ‘NLT % (Q) at 30 minutes’ for celecoxib.

Dissolution of Pivotal Clinical Study Batch and Registration Batches

Dissolution profiles for the pivotal bioequivalence study batch (BY261015A) obtained using the
originally proposed dissolution method (b) (4) rpm) are provided in Table 11. Dissolution data for
individual units are provided in .xpt format in Module 3.2.P.2.1 1 .

Table 11: Dissolution Results for Batch BY261015A (Pivotal Bio Batch)
(b) (4)

1 GlobalSubmit Review Link: Application 210045 - Sequence 0001 - Dissolution Data xpt

17
Dissolution profiles for the registration batches of each of the strengths are provided in Figure 13
(celecoxib) and Figure 14 (amlodipine).

Figure 13. Dissolution of celecoxib from the registration stability batches

(b) (4)

Figure 14. Dissolution of amlodipine from the registration stability batches

(b) (4)

It is noted that the above dissolution studies were performed with the originally proposed dissolutio n
method with the paddle speed of (b) (4) rpm; however, the proposed FDC product is expected to show
similar dissolution profiles for amlodipine and celecoxib with the newly proposed and agreed to
dissolution method with the paddle speed of 75 rpm.

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5. BRIDGING STUDIES

Via an IR (dated 12/29/2017), the Applicant was requested to clarify if there are any changes in drug
product composition, its manufacturing process or site, or API suppliers between the pivotal bio-batch
and the proposed commercial product. In a response dated 02/05/2018, the Applicant stated that there
are no changes in terms of the drug product composition, its manufacturing process or site, or API
suppliers between the pivotal clinical study batch and the proposed commercial product. Therefore, no
bridging studies are needed.

6. BIOWAIVER REQUEST

The proposed product is an FDC product of amlodipine/celecoxib manufactured at three strengths : 2.5
mg/200 mg, 5 mg/200 mg, and 10 mg/200 mg. following the FDA’s recommendation provided at the
pre-NDA meeting for IND112830 held in April 11, 2016.

The proposed product does not have classical proportionality between the strengths, due to the constant
celecoxib dosage of 200 mg across all strengths (Table 1). (b) (4)

The Applicant adopted the approach of bracketing for the in vivo pharmacokinetic studies
and provided data to demonstrate bioequivalence between the highest (10 mg/200 mg) and the lowest
(2.5 mg/200 mg) proposed strengths and their corresponding listed drug products, to support the
biowaiver request for the 5 mg/200 mg (middle) strength tablets.
The provided in vivo data for the highest strength (10 mg/200 mg) and the lowest strength (2.5 mg/200
mg) indicate that these two strengths of the proposed FDC product are bioequivalent to the
corresponding strengths of the LDs (refer to the Office of Clinical Pharmacology review for assessment
of the BE studies). To support the biowaiver request for the intermediate strength, the Applicant
provided comparative dissolution data only with the originally proposed dissolution method (b) (4) rpm),
but did not provide multi- media dissolution data. Therefore, via an IR dated 12/29/2017, the Applicant
was recommended to provide multi- media dissolution data to support the biowaiver request for the
intermediate strength of the proposed product. It was stated in the IR that (b) (4)

In a response dated 02/05/2018, the Applicant provided comparative dissolution data for the 200mg/10
mg and 200 mg/5 mg strengths of the proposed product in three different pH media, each with 0.5%
SLS. The dissolution data for celecoxib and amlodipine are summarized in Figure 15 and Figure 16,
respectively. (b) (4)

The data are summarized in Table 12.

19
Figure 15: Comparative Dissolution of 200 mg/10 mg and 200 mg/5 mg KIT-302 Tablets –
Celecoxib Component

(b) (4)

20
Figure 16: Comparative Dissolution of 200 mg/10 mg and 200 mg/5 mg KIT-302 Tablets –
Amlodipine Component

(b) (4)

21
 Table 12: Comparative Amlodipine Dissolution Results for High Strength (10 mg/200 mg) KIT
302 Tablets (Lot BY261015A; Pivotal Bio Batch) and Mid Strength (5 mg/200 mg) KIT-302
Tablets (Lot BY291015A)
(b) (4)

The comparative dissolution data provided by the Applicant show similar profiles in multi- media (b) (4)
between the highest strength (10 mg/200 mg) and the middle strength (5 mg/200
mg) of the proposed product. Also, the Applicant provided data show similar dissolution across all
three strengths of the proposed product in the proposed dissolution medium (Figures 13 and 14).

Overall, the provided data/ information support the Applicant’s biowaiver request for the middle
strength, Amlodipine Besylate and Celecoxib Tablets, 5 mg/200 mg. Therefore, the Applicants
biowaiver request is granted.

7. CONCLUSIONS AND RECOMMENDATION

From a Biopharmaceutics perspective, NDA 210045 for Amlodipine Besylate and Celecoxib Tablets,
5 mg/200 mg, 5 mg/200 mg, 10 mg/200 mg, is recommended for APPROVAL.

The Applicant has agreed to the following PMC in the response dated 04/13/2018 and has committed
to submitting the requested data/information in a final study report (b) (4)

22
 Agreed-Upon Studies to be Performed Under the PMC
(b) (4)

 (b) (4)

Submit the final report (b) (4)

23
Kaushalkumar Digitally signed by Kaushalkumar Dave
Dave Date: 4/27/2018 11:23:47AM
GUID: 5575db68006e2262805f2e6449c54250

Jing Digitally signed by Jing Li

Li Date: 4/27/2018 11:39:43AM
GUID: 508da7420002bb05ac913303b23c39bb
Wendy Digitally signed by Wendy Wilson- Lee
Wilson- Lee Date: 4/27/2018 12:18:07PM
GUID: 50816dbc000085595ca3284bbca465a8