CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`204654Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`
`NDA Number: 204654
`
`Stamp Date: 09/28/2012
`
`Applicant: Warner Chilcott Company, LLC
`
`Drug Name:
` (norethindrone acetate and ethinyl estradiol chewable tablets, ethinyl estradiol tablets, and
` ferrous fumarate tablets)
`
`On initial review of the NDA/BLA application for filing:
`
`
`
`
`
`
`Yes No N/A
`
`Comment
`
`
`Content Parameter
`Criteria for Refusal to File (RTF)
`1 Has the applicant submitted bioequivalence data comparing to-be-
`marketed product(s) and those used in the pivotal clinical trials?
`2 Has the applicant provided metabolism and drug-drug interaction
`information?
`
`3 Has the sponsor submitted bioavailability data satisfying the CFR
`requirements?
`4 Did the sponsor submit data to allow the evaluation of the validity
`of the analytical assay?
`5 Has a rationale for dose selection been submitted?
`6
`Is the clinical pharmacology and biopharmaceutics section of the
`NDA organized, indexed and paginated in a manner to allow
`substantive review to begin?
`Is the clinical pharmacology and biopharmaceutics section of the
`NDA legible so that a substantive review can begin?
`Is the electronic submission searchable, does it have appropriate
`hyperlinks and do the hyperlinks work?
`
`7
`
`8
`
`x
`
`
`
`x
`
`x
`
`
`x
`
`x
`
`x
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`x
`
`
`
`
`
`x
`
`
`
`
`
`
`
`
`x
`
`
`
`x
`
`
`
`new
`formulation,
`use the
`information
`from the
`reference
`product
`Pivotal study
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1
`
`
`Criteria for Assessing Quality of an NDA (Preliminary Assessment of Quality)
` Data
`9 Are the data sets, as requested during pre-submission discussions,
`submitted in the appropriate format (e.g., CDISC)?
`If applicable, are the pharmacogenomic data sets submitted in the
`appropriate format?
`
` Studies and Analyses
`Is the appropriate pharmacokinetic information submitted?
`
`x
`
`
`
`x
`
`10
`
`
`
`11
`
`Has the applicant made an appropriate attempt to determine
`reasonable dose individualization strategies for this product (i.e.,
`appropriately designed and analyzed dose-ranging or pivotal
`studies)?
`
`
`
`
`
`12
`
`
`
`Reference ID: 3221666
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
`x
`
`x
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`x
`
`x
`
`x
`
`x
`
`
`
`
`
`x
`
`
`
`
`
`
`
`The Sponsor
`requests a full
`pediatric waiver
`for pre-
`menarcheal
`children
`
`
`
`
`
`
`
`Are the appropriate exposure-response (for desired and undesired
`effects) analyses conducted and submitted as described in the
`Exposure-Response guidance?
`Is there an adequate attempt by the applicant to use exposure-
`response relationships in order to assess the need for dose
`adjustments for intrinsic/extrinsic factors that might affect the
`pharmacokinetic or pharmacodynamics?
`Are the pediatric exclusivity studies adequately designed to
`demonstrate effectiveness, if the drug is indeed effective?
`Did the applicant submit all the pediatric exclusivity data, as
`described in the WR?
`
`
`
`
`
`13
`
`
`
`14
`
`
`
`
`
`15
`
`16
`
`17
`
`
`
`18
`
`Is there adequate information on the pharmacokinetics and
`exposure-response in the clinical pharmacology section of the label?
`
` General
`Are the clinical pharmacology and biopharmaceutics studies of
`appropriate design and breadth of investigation to meet basic
`requirements for approvability of this product?
`Was the translation (of study reports or other study information)
`from another language needed and provided in this submission?
`
`
`
`19
`
`
`IS THE CLINICAL PHARMACOLOGY SECTION OF THE APPLICATION FILEABLE? ___Yes___
`
`The following are reviews issues to be conveyed to the sponsor:
`
`The labeling of the new dosing instruction to include volume and type of liquid will be a review issue.
`
`
`
`
`
`
`Li Li
`Reviewing Clinical Pharmacologist
`Myong Jin Kim
`
`
`Team Leader/Supervisor
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`10/26/2012
`Date
`10/26/2012
`Date
`
`
`
`Reference ID: 3221666
`
`2
`
`

`

`Filing Memo
`
`Clinical Pharmacology Review
`
`NDA:
`
`204654
`
`Compound:
`
`Sponsor:
`Date:
`
`W" (norethindrone acetate and ethinyl estradiol chewable tablets, ethinyl estradiol tablets,
`and ferrous fumarate tablets)
`Warner Chilcott Company. LLC
`10/26/2012
`
`Reviewer:
`
`Li Li, PhD.
`
`Introduction:
`
`(I!) (4)
`
`plication (NDA) for a combination oral contraceptive (COC)
`The Sponsor submitted a New Drug
`)(4) is
`The dose and dosing regimen of
`0 Cycle Days 1-24: one mint-flavored chewable tablet containing 1 mg norethindrone acetate (NETA)/ 10
`pg ethinyl estradiol (EE) (referred to as
`(m4) 1/10 Tablet)
`0 Cycle Days 25-26: one 10 pg EE tablet Referred to as WC3016 EE10 Tablet)
`0 Cycle Days 27-28: one inactive tablet containing ferrous fumarate
`One tablet is to be taken daily for 28 consecutive days.
`
`”(”has the same NETA/ EE dose and dosing regimen as the reference product Lo Loestrin Fe (NDA
`022501, Warner Chilcott Company, approved on October 21, 2010). The difference is in the mode of
`administration for tablets in the first 24-day of each cycle. In particular,
`"’"0 1/10 tablet can be “chewed” 8
`whereas WC3016 1/10 tablet in L0 Loestrin Fe should be “swallowed whole”. In addition, a
`M“) and Spearmint flavor is added to
`"M" 1/10 tablet to enhance the chewability of the formulation.
`The 10 ug EE tablets and ferrous fumarate tablets in
`M" are identical to those in L0 Loeslrin Fe.
`
`The Sponsor seeks the approval of
`(NE) and EE exposure between
`(Study PR12111).
`
`(5)“) based on the demonstration of bioequivalence (BE) in norethindrone
`«9(4) 1/10 chewable tablets and WC3016 1/10 tablets in L0 Loestn'n Fe
`
`M"
`Clinical Development of
`This application contains a full report of:
`0 BE and food effect study (Study PR—12111):
`A Randomized, Single-Dose, Three-Way Crossover Study conducted in healthy female volunteers to
`o assess the BE in NE and EE exposure from
`(mo 1/10 chewable tablets and the approved Lo
`Loestrin Fe (WC3016 1/10) tablets
`M" 1/10 chewable tablets
`o assess the effect of food on bioavailability ofNE and EE from the
`Food effect study on WC3016 EE10 tablet (Study PR-l4106, previously submitted under NDA 022501)
`Single- and multiple-dose study of L0 Loesuin Fe (WC3016 1/10) tablet (Study PR-l4206, previously
`submitted under NDA 022501)
`0 Oral safety study of
`“"4’chewable tablets (Study PR-10007)
`
`0
`0
`
`Drug Product Formulation:
`The
`(5)“) 1/10 chewable tablet formulation was based on the formulation for the approved WC3016 1/ 10
`tablets. The
`(m4) 1/ 10 chewable tablet formulation has added flavor and
`(mo
`
`"m" l/10 chewable
`mannitol. A comparison of the unit-dose composition for the
`tablet formulation and the reference product, WC3016 1/10 tablet formulation is provided in Table 1.
`
`Reference ID: 3221 666
`
`

`

`(5) (4’ 1f 10 chewable tablets
`
`(Formulation
`
`(10(4)
`
`Lactose Monoh drate.
`
`Mieroe
`
`stalline Cellulose
`
`FD&C Blue #1 Aluminum Lake
`
`S . armint Flavor
`
`0') (4)
`
`Ma y: esium Stearate
`
`Sodium Starch G1 colate
`
`(It) (4)
`
`BE Assessment
`
`A single-dose. three way-crossover study was conducted in 42 healthy female volunteers. All subjects
`received the following 3 treatments:
`0 Treatment A: WC3016 1/10 tablet administered under fasted conditions
`
`o) (4) 1/ 10 chewable tablet administered under fasted conditions
`0 Treatment B:
`M" 1/10 chewable tablet administered with a high fat meal
`0 Treatment C:
`All tablets were administered orally with about 240 mL water following at least a 10-hour fast or following
`consumption of a standard high fat meal (Treatment C). Blood samples (10 ml.) were collected at predose and 0.5,
`l. 1.5. 2. 2.5. 3. 4. 6. 8. 12. 16. 24. 36. 48 and 60 hours postdose. Treatment periods were separated by at least 7
`days.
`
`(mo
`Per Sponsor, statistical analysis on PK parameters (i.e.. Cmax and AUC) of NE and EE indicated that the
`chewable 1/10 tablet is bioequivalent to WC3016 1/10 tablet. When
`M" 1/10 chewable tablets were
`administered with food, Cmax values were decreased by 46% for NE and 41% for BB. The extent of NE and EE
`absorption was not significantly different.
`
`Absorption, Distribution, Metabolism, and Excretion (ADME)
`Specific studies describing the ADME of
`(mo were not conducted. The Sponsor is proposing to use the
`available information of the reference product (i.e.. Lo Loestrin Fe).
`
`Drug-Drug Interactions:
`No DDI studies were conducted with
`
`M4)
`
`Specific Populations:
`0
`Pediatric use: No pediatric studies were conducted; the Sponsor requests a full waiver of the requirement
`for pediatric studies associated with the submission of this NDA
`Geriatric use: No geriatric studies were conducted
`Renal or hepatic impairment: No studies were conducted in patients with renal or hepatic impairments
`Contraindicated for pregnant women
`
`Bioanalytical Method:
`
`Reference ID: 3221 666
`
`

`

`Plasma NE and EE concentrations were determined using GC/MS method; the bioanalytical work was performed
`by
`one
`
`Recommendation:
`
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology 3 finds that the Clinical Pharmacology
`section for NBA 204654 is fileable.
`
`Office of Scientific Investigation (OSI) Inspection Request
`Study PR—12111 (pivotal BE study) was conducted by
`bioanalytical work was done by
`inspections of these sites and that no major issues were identified.
`sites will not requested.
`
`(no) The
`(”m Given that there were several recent
`the inspection of the clinical and bioanalytical
`
`Reviewer’s Comments:
`
`(m4) 1/10 tablet) was taken with 240 mL water. This is not consistent
`In the BE study. the chewable tablet (
`(”m It should be noted that
`with the proposed drug product label, i.e..
`some liquids such as grapefruit juice may affect the CYP3A4 activity and in turn change the systemic exposure of
`NE and EE.
`
`(no) Given the minor changes in the
`M" 1/10 tablet can also be taken as
`Per product label,
`formulation, i,e, added flavor and
`on»
`a dedicated BE study may not be necessary. However, the final
`decision will be made by the CMC reviewer.
`
`(”m 1/10 is identical to the to-be-marketed (TBM) formulation. The TBM batch
`The clinical formulation for
`scale is
`(mo larger than that of clinical study tablets. Per CMC lead Dr. Donna Chrismer, less than
`“M" of
`scale change is acceptable without the need for comparative dissolution testing.
`
`Incurred Sample Reanalysis aSR) was conducted in the BE study.
`
`Reference ID: 3221 666
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LI LI
`11/27/2012
`
`MYONG JIN KIM
`11/27/2012
`
`Reference ID: 3221666
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW ADDENDUM
`
`
`NDA 204654
`
`Brand Name
`Generic Name
`
`Reviewer
`Acting Team Leader
`OCP Division
`OND Division
`Sponsor
`Submission Type
`Formulation; Strengths;
`Regimen
`
`Proposed Indication
`
`09/28/12, 11/27/12, 01/23/13, 04/04/13,
`05/18/13, 05/22/13, 07/16/13, 07/23/13
`
`Submission
`Date(s)
`Lo Minastrin Fe
`Norethindrone acetate (NA) / Ethinyl estradiol
`(EE) / Ferrous fumarate (Fe)
`Li Li, PhD
`Myong Jin Kim, PharmD
`Division of Clinical Pharmacology 3
`Division of Bone, Reproductive and Urologic Products
`Warner Chilcott Company, LLC
`Original
`One chewable tablet containing 1 mg NA/10 μg EE for 24 days,
`followed by one tablet containing 10 μg EE for 2 days and one
`tablet containing 75 mg Fe for 2 days (28 day regimen), daily
`oral administration
`Prevention of pregnancy
`
`Executive Summary
`
`
`
` 1
`
`
`The Clinical Pharmacology review of NDA 204654 (DARRTS, June 20, 2013) stated that NDA
`204654 was acceptable provided that an agreement is reached between the sponsor and the
`Division regarding the language in the package insert labeling. The final agreement was reached
`on July 23, 2013 and there are no pending issues from the Office of Clinical Pharmacology. The
`highlights of the prescribing information and Clinical Pharmacology relevant sections of the final
`agreed upon package insert labeling are included in Section 2 of this addendum.
`
`1.1
`Recommendation
`The Division of Clinical Pharmacology-3, Office of Clinical Pharmacology finds the NDA
`204654 acceptable.
`
`
`
`
`Reference ID: 3346290
`
`1
`
`8 Pags of Draft Labeling have been
`Withheld in Full as b4 (CCI/TS)
`immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LI LI
`07/24/2013
`
`MYONG JIN KIM
`07/24/2013
`
`Reference ID: 3346290
`
`

`

`Clinical Pharmacology Review
`
`204654
`09/28/12, 11/27/12, 01/23/13, 04/04/13, 05/18/13,
`05/22/13
`TBD
`Norethindrone acetate (NA) / Ethinyl estradiol
`(EE) / Ferrous fumarate (Fe)
`Li Li, Ph.D
`Myong Jin Kim, Pharm. D
`Division of Clinical Pharmacology III
`Division of Bone, Reproductive and Urologic Products
`Warner Chilcott Company, LLC
`Original NDA; Standard review
`022501, Lo Loestrin Fe® Tablets
`One chewable tablet containing 1 mg NA/10 μg EE for 24
`days, followed by one tablet containing 10 μg EE for 2
`days and one tablet containing 75 mg Fe for 2 days (28 day
`regimen), daily oral administration
`Prevention of pregnancy
`
`
`NDA Number:
`Submission Date:
`
`Brand Name:
`Generic Name:
`
`
`
`OCP Reviewer:
`OCP Team Leader:
`OCP Division:
`OND Division:
`Sponsor:
`Submission Type:
`Relevant NDA:
`Formulation; strength:
`
`
`Indication:
`
`
`
`Table of Contents
`
` 1
`
` Executive Summary .........................................................................................................................2
`1.1
`Recommendations ...............................................................................................................2
`1.3
`Summary of Clinical Pharmacology Findings ....................................................................2
`2 Question Based Review ...................................................................................................................4
`2.1
`General Attributes ...............................................................................................................4
`2.2
`General Clinical Pharmacology...........................................................................................6
`2.3
`Intrinsic Factors.................................................................................................................. 9
`2.4
`Extrinsic Factors..................................................................................................................9
`2.5
`General Biopharmaceutics.................................................................................................11
`2.6
`Analytical Section .............................................................................................................11
`3 Detailed Labeling Recommendations ............................................................................................12
`4 Appendix
`4.1 Individual Study Review..........................................................................................................13
`
`
`
`
`Reference ID: 3328945
`
` 1
`
`

`

`
`
`Executive Summary
`The Sponsor submitted an orignial New Drug Application (NDA) for a combination oral contraceptive
`(COC)
` on September 28, 2012.
`
` are as follows:
`The dose and dosing regimen of
`• Cycle Days 1-24: one mint-flavored, chewable tablet containing 1 mg NA/10 µg EE (referred to
`as
` 1/10 Tablet)
`• Cycle Days 25-26: one 10 µg EE tablet
`• Cycle Days 27-28: one inactive tablet containing 75 mg Fe
`One tablet is to be taken daily for 28 consecutive days without regard to meals.
`
`
`has the same NA/ EE dose and dosing regimen as the reference product Lo Loestrin Fe® (NDA
`022501, Warner Chilcott Company, approved on October 21, 2010). The difference is in the mode of
`administration for tablets in the first 24-day of each cycle. Specifically,
` 1/10 tablet containing 1
`mg NA/10 µg EE should be “chewed” and “swallowed” whereas the respective tablets in Lo Loestrin
`Fe® (referred to as WC3016 1/10 tablets) should be “swallowed whole”. The formulations of 10 µg EE
`tablets and ferrous fumarate tablets in
` are identical to those in Lo Loestrin Fe® and are to be
`administered as “swallowed whole”.
`
` based on the demonstration of bioequivalence (BE) in
`The Sponsor seeks the approval of
`norethindrone (NE) and EE exposure between
` 1/10 chewable tablets and WC3016 1/10 tablets
`in Lo Loestrin Fe® (Study PR-12111). In addition, the effect of food on the bioavailability (BA) of NE
`and EE from
` 1/10 chewable tablets was evaluated in the same study.
`
`For the pivotal BE study (Study PR-12111), a formal consult to the Office of Scientific Investigations
`(OSI) was made for inspections of the clinical and bioanalytical study sites.
`
`1.1
`Recommendation
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology 3 (OCP/DCP3) finds NDA
`204654 acceptable provided that agreement is reached between the Sponsor and the Division regarding
`the language in the package insert.
`
` •
`
`Phase IV Commitment/Requirement
`
`Summary of Important Clinical Pharmacology and Biopharmaceutics Findings
`
`
`None
`
`1.3
`
` 1/10 chewable tablets and WC3016 1/10 tablets in Lo Loestrin Fe ®
`BE assessment of
`Study PR-12111 demonstrated the BE in NE and EE exposure between
` 1/10 chewable tablets
`and WC3016 1/10 tablets (Lo Loestrin Fe®) following a single dose administration under a fasting
`condition in 38 healthy premenopausal women. The 90% confidence intervals (CI) for the test
`1/10) to reference (WC3016 1/10) ratio in Cmax, AUC0-t, and AUC0-inf are within the 80.00% to 125.00%
`BE limit for both NE and EE (Table 1).
`
`Table 1 BE analysis of NE and EE PK parameters following a single dose administration of
`
`1/10 chewable tablets (Test) or a WC3016 1/10 tablets in Lo Loestrin Fe® (Reference) under a fasting
`condition in 38 healthy female volunteers
`
`
`
`
`Reference ID: 3328945
`
` 2
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`102.52
`
`109.74
`
`102.79
`109.85
`
`105.38
`
`117.20
`
`97.52— 107.79
`
`100.17— 120.22
`
`97.76—108.07
`102.84—117.34
`
`97.14 — 114.31
`
`111.22 — 123.50
`
`Amlyte
`
`“WAUCM(pg-hr/mL
`. AUCm(pghr/mL)
`
`Aucflw-hdmL)
`
`Cm(pg/mL)
`
`AIJChf(pg'lldmL)
`
`Cm (pg/mL)
`
`Absorption, Distribution, Metabolism, and Excretion (ADME)
`(mo 1/10 chewable tablets
`The Sponsor determined NE and EE PK profiles after a single dose of
`under fasting and fed conditions in study PR-12111. The respective PK parameters are summarized in
`Table 2. No other specific studies describing the DME of NE and BB were conducted.
`
`Table 2 Arithmetic means (%CV) of PK parameters of NE and EE following a single dose administration
`of
`(5)14) 1/10 chewable tablets in healthy female subjects under a fasting condition (N=38, data from
`study PR-121 l l)
`
`—“—
`
`
`
`median (range)
`
`Food Effect:
`A high fat meal reduced the rate, but not the extent of NE and EE absorption from WC 00(4) 1/10
`chewable tablet (Study PR-12111) compared to a fasting condition. Specifically, a high fat meal reduced
`the mean NE and EE szx values by 46 and 41%. respectively and increased the median NE and EE t1m
`values by 2.5 hours. However. the 90% CI for test (fed) to reference (fasted) ratio in NE and EE AUC
`values were within the 80.00% to 125.00% BE limits.
`
`Drug—Drug Interactions:
`one tablets. The Sponsor is proposing to use the
`No new DDI studies were conducted for
`information fiom Lo Loestrin Fe® for their product labeling.
`
`Specific Populations:
`Renal or Hepatic Impairment
`No studies have been conducted to evaluate the effect of renal or hepatic impairment on the disposition of
`L0 Loestrin Fe® or the current product. In general, steroid hormones may be poorly metabolized in
`patients with impaired liver function. Lo Loestrin Fe® tablets are contraindicated for women with liver
`tumors or liver disease.
`
`Pediatric subjects
`
`Reference ID: 3328945
`
`

`

`The Sponsor has submitted a pediatric waiver request. Under the Pediatric Research Equity Act (PREA)
`(21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new
`dosing regimens, or new routes of administration are required to contain an assessment of the safety and
`effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is
`waived, deferred, or inapplicable. Because the current submission is just for a new mode of administration,
`this NDA is not subject to PREA.
`
`Bioanalytical Method Validation:
`Plasma concentrations of NE and EE were determined by a validated Gas Chromatography/Mass
`Spectrometry (GC/MS) method. Acceptance criteria and assay performance for are found to be acceptable.
`
`An OSI consult requesting inspections of the clinical and bioanalytical sites of the pivotal BE study PR-
`12111 was made on January 18, 2013. There were no significant objectionable issues identified in the
`clinical site of the BE study. However, following the inspection on the analytical site in
`
`, Form FDA-483 was issued on April 19, 2013 based on the observation
`listed below: “Not all aspects of study conduct were documented. For example: failure to maintain
`documentation for individual QC sets used during sample processing.”
` submitted a written
`response to Form FDA-483 on May 14, 2013. Following the review of the Form FDA 483 and the
`response from
` OSI recommended that that the clinical and analytical data generated for study
`PR-12111 were not affected by the cited deficiency and thus are accepted for further agency review.
`Details of the OSI inspection findings can be found in Dr. Adrindam Dasgupta OSI consult review dated
`May 30, 2013 in DARRTS.
`
`QUESTION BASED REVIEW
`
` 2
`
`
`
`2.1 GENERAL ATTRIBUTES
`2.1.1 What pertinent regulatory background or history contributes to the current assessment of
`the Clinical Pharmacology and Biopharmaceutics of this drug?
`
`
`The Sponsor submitted an NDA for a 28-day regimen COC
`. It has the same NA/ EE dose and
`dosing regimen as the reference product Lo Loestrin Fe® (NDA 022501, approved on October 21, 2010).
`The difference is in the mode of administration for tablets in the first 24-day of each cycle. In particular,
` 1/10 tablet should be “chewed” and “swallowed” whereas WC3016 1/10 tablet in Lo Loestrin
`Fe® should be “swallowed whole”. In addition, a
`and spearmint flavor are added to
`
`1/10 chewable tablets to enhance the chewability of the formulation. The 10 µg EE tablets and ferrous
`fumarate tablets in
` are identical to those in Lo Loestrin Fe® and are to be administered as
`“swallowed whole”.
`
` based on the demonstration of BE in NE and EE exposures
`The Sponsor seeks the approval of
`between
`1/10 chewable tablets and WC3016 1/10 tablets in Lo Loestrin Fe® (Study PR-12111).
`
`2.1.2 What are the highlights of the chemistry and physical-chemical properties of the drug
`substance as they relate to clinical pharmacology and biopharmaceutics review?
`
`
`Active substance:
`The chemical name of NA is [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-] and the
`empirical formula is C22H28O3. The structural formula is shown in Figure 1.
`
`
`Reference ID: 3328945
`
` 4
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Figure 1 Chemical structure of NA
`
`
`The chemical name of EE is [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-] and the
`empirical formula is C20H24O2. The structural formula is shown in Figure 2.
`
`Figure 2 Chemical structure of EE
`
`
`
`
`
`
`
`2.1.3 What are the proposed mechanism of action and therapeutic indication?
`Indication:
`Prevention of pregnancy
`
`Mechanism of Action:
`COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible
`mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial
`changes that reduce the likelihood of implantation.
`
`2.1.4 What are the proposed dose and dosing regimen?
`The proposed dose and dosing regimen of
` are as follows:
`• Cycle Days 1-24: one mint-flavored, chewable tablet containing 1 mg NA/10 µg EE (referred to
`as
` 1/10 Tablet)
`• Cycle Days 25-26: one 10 µg EE tablet (Referred to as WC3016 EE10 Tablet)
`• Cycle Days 27-28: one inactive tablet containing 75 mg Fe
`One tablet is to be taken daily for 28 consecutive days without regard to meals.
`
`2.1.5 What clinical and clinical pharmacology data are submitted to support the approval of
`?
`This application contains a full report of:
`• BE and food effect study (Study PR-12111):
`A Randomized, Single-Dose, Three-Way Crossover Study conducted in healthy female
`
`Reference ID: 3328945
`
` 5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`volunteers to
`o assess the BE in NE and EE exposure from
`WC3016 1/ 10 tablets in L0 Loestrin Fe®
`
`M" 1/10 chewable tablets and the
`
`o assess the effect of food on BA of NE and EE from the
`
`(mo 1/ 10 chewable tablets
`
`0
`
`Food effect study on WC3016 EE10 tablet (Study PR-l4106, previously submitted under NDA
`022501)
`
`0
`
`Single— and multiple-dose study of L0 Loestrin Fe (WC3016 1/10) tablet (Study PR-l4206,
`previously submitted under NDA 022501)
`0 Oral safety study of
`“W’chewable tablets (Study PR—10007)
`
`The Sponsor is relying on the previous Phase 3 study of L0 Loestn'n Fe® tablets for the demonstration of
`safety and efficacy.
`
`2.2
`
`GENERAL CLINICAL PHARMACOLOGY
`
`"M 1/10 chewable tablet BE to the WC3016 1/10 tablet in L0 Loestrin Fe®?
`Is
`2.2.1
`Yes. Study PR-12111 demonstrated the BE in NE and EE exposure between
`(m4) 1/10 chewable
`tablets and WC3016 l/10 tablets in L0 Loestrin Fe®.
`
`Study Desig:
`This is a single-dose, three way-crossover study conducted in 42 healthy female volunteers. All subjects
`received the following 3 treatments:
`0 Treatment A: WC3016 1/10 tablet administered under fasted conditions
`0 Treatment B:
`“M" 1/10 chewable tablet administered under fasted conditions
`0 Treatment C:
`(m4) 1/10 chewable tablet administered with a high fat meal
`All tablets were administered orally with about 240 mL water following at least a 10-hour fast (Treatment
`A and B) or following consumption of a standard high fat meal (Treatment C). Blood samples (10 mL)
`were collected at predose and 0.5, l, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48 and 60 hours postdose.
`Treatment periods were separated by at least 7 days.
`
`Study Results:
`(I'm 1/10 chewable tablet) and reference (WC3016 1/10 tablet in L0
`As shown in Figure 3. the test
`Loestrin Fe®) products displayed similar PK profiles. The 90% CI for test to reference ratio in Cm,
`AUCm, and AUCO—inf are within the BE limits of 80.00 to 125.00% for both NE and EE (Table 3).
`
`Figure 3: Mean NE and EE Concentration-Time Profiles following a single dose of a
`tablet (Test) or a WC3016 tablet Reference) to fasted healthy female volunteers (N=3 8)
`
`(b)(4)
`
`chewable
`
`Reference ID: 3328945
`
`

`

`
`
`NEConcettration[pgmL]
`
`~8- A: W63016 tablet fasted -n- B: WC3064 tablet lasted
`
`Time (hr)
`
`NH910
`
`
`
`EECementration[pg/mL) NO
`
`
`
`
`
`0 ii
`0
`
`10
`
`20
`
`I
`30
`Time (hr)
`
`40
`
`50
`
`60
`
`-e- A: WC3016 tablet tested -9- B: WC3064 tablet fasted
`
`“M" 1/10 chewable
`Table 3 BE analysis of NE and EE PK parameters following a single dose of
`tablets Test or a WC3016 1/10 tablets
`' eference to fasted health female volunteers
`=38
`
`97.52 — 107.79
`
`38390
`
`37445
`
`102.52
`
`Reference ID: 3328945
`
`

`

`(5)14) 1/10 chewable tablet?
`2.2.2 What are PK characteristics of NE and EE from
`The Sponsor determined NE and EE PK profiles after a single dose of
`"M” 1/10 chewable tablets
`under fasting and fed condition in study PR-12111. The respective PK parameters were summarized in
`Table 4 and Table 5. No other specific studies describing the DME of NE and BB were conducted.
`
`Table 4 Arithmetic means (%CV) of PK parameters of NE and EE following a single dose administration
`of
`M" 1/10 chewable tablets to fasted health female sub'ects
`=38. data from study PR-121 l 1)
`
`n
`
`median (range)
`
`Food Effect: A High fat meal reduced the rate, but not the extent of NE and EE absorption from (we)
`1/10 chewable tablets (Study PR-12111).
`M“) 1/10 chewable tablets can be taken without
`regard to meal.
`
`Study Design: Refer to Section 2.2.1
`
`Study Results:
`High fat meal reduced the mean NE and EE Cmax values by 46 and 41%. respectively and increased the
`median NE and EE tmax values by 2.5 hours. indicating a decreased rate of absorption in the presence of
`food. However. the extent of NE and EE absorption was not afl'ected by food as the 90% CI for the test
`(fed) to reference (fasted) ratio in NE and EE AUC were within the 80.00% to 125.00% BE limits
`(Table 5).
`
`Table 5 Statistical analysis of NE and EE PK parameters following a single dose administration of a
`M" 1/10 chewable tablets to healthy female volunteers under fasted (reference) and fed (test)
`conditions (N=3 7)
`
`A...
`
`NE
`
`mm!
`
`Ratio
`
`«mm m
`
`AUCm -hr/mL
`(pg
`)
`
`41687
`
`37706
`
`110.56
`
`105.02—116.39
`
`
`
`—————
`298
`294
`101.38
`93.14— 110.35
`
`393
`
`22.4
`
`360
`
`37.7
`
`109.02
`
`98.12 — 121.12
`
`59.32
`
`54.29 — 64.82
`
`4.00 ( 1.50— 12.00) 1.50 (0.50 — 2.50)
`
`. Median (range)
`
`Reference ID: 3328945
`
`

`

`
`Distribution
`Based on Lo Loestrin Fe® labeling, volume of distribution of NE and EE ranges from 2 to 4 L/kg. Plasma
`protein binding of both steroids is extensive (>95%); NE binds to both albumin and SHBG, whereas EE
`binds only to albumin. Although EE does not bind to SHBG, it induces SHBG synthesis.
`
`Metabolism
`Based on Lo Loestrin Fe® labeling, NE undergoes extensive biotransformation, primarily via reduction,
`followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are
`sulfates, with glucuronides accounting for most of the urinary metabolites. A small amount of NA is
`metabolically converted to EE.
`EE is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide.
`Sulfates are the major circulating conjugates of EE and glucuronides predominate in urine. The primary
`oxidative metabolite is 2-hydroxy EE, formed by the CYP3A4 isoform of cytochrome P450. Part of the
`first-pass metabolism of EE is believed to occur in gastrointestinal mucosa. EE may undergo
`enterohepatic circulation.
`
`Excretion
`Based on Lo Loestrin Fe® labeling, NE and EE are excreted in both urine and feces, primarily as
`metabolites. Plasma clearance values for NE and EE are similar (approximately 0.4 L/hr/kg). Elimination
`half-lives of NE and EE following administration of tablets containing the combination of 1 mg NA and
`10 µg EE are approximately 10 hours and 16 hours, respectively.
`
`2.3 INTRINSIC FACTORS
`2.3.1 What intrinsic factors (age, race, weight, and organ dysfunction) influence exposure (PK
`usually) and/or response, and what is the impact of any differences in exposure on efficacy or safety
`responses?
`
`Renal or Hepatic Impairment
`No studies have been conducted to evaluate the effect of renal or hepatic impairment on the disposition of
`Lo Loestrin Fe® or current product.
`In general, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or
`chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of
`liver function return to normal and COC causation has been excluded. Lo Loestrin Fe® tablets are
`contraindicated for women with liver tumors or liver disease.
`
`Pediatric subjects
`The Sponsor has submitted pediatric waiver request. Under the PREA (21 U.S.C. 355c), all applications
`for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the product for the
`claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable.
`Because the current submission is just for a new mode of administration, this NDA is not subject to
`PREA.
`
`2.4 EXTRINSIC FACTORS
`The Sponsor is proposing to use the following publicly
`No formal studies were conducted with
`available information from Lo Loestrin Fe® label.
`
`Changes in contraceptive effectiveness associated with co-administration of other products:
`
`Reference ID: 3328945
`
` 9
`
`(b) (4)
`
`

`

`If a woman on hormon