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

`

` Daniel Davis, MD
`
`Clinical Review NDA 204654
`norethindrone acetate 1 mg/ethinyl estradiol 0.01 mg chewable tablet
`
`
`
`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 204654
`Priority or Standard Standard
`Submit Date(s) September 27, 2012
`Received Date(s) September 28, 2012
`PDUFA Goal Date July 28, 2013
`Division / Office DBRUP/ODE III
`Reviewer Name(s) Daniel Davis, MD
`Review Completion Date June 28, 2013
`
`Established Name norethindrone acetate/ethinyl
`estradiol (EE) chewable
`tablets, ethinyl estradiol tablets
`and ferrous fumarate (FF)
`tablets
`to be determined
`(Proposed) Trade Name
`Therapeutic Class Hormonal contraception
`Applicant Warner Chilcott Company, LLC
`
`Formulation(s) Chewable tablet; tablet
`Dosing Regimen 1 active chewable tablet for 24
`days; 1 EE tablet for 2 days;
`1 iron tablet for 2 days
`Indication(s) Prevention of pregnancy
`Intended Population(s) Women of reproductive age
`
`
`Reference ID: 3336601
`
`1
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`

`

` Daniel Davis, MD
`
`Clinical Review NDA 204654
`norethindrone acetate 1 mg/ethinyl estradiol 0.01 mg chewable tablet
`
`
`
`Table of Contents
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 5
`
`1.1 Recommendation on Regulatory Action ............................................................. 5
`1.2 Risk Benefit Assessment .................................................................................... 5
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 5
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 5
`
`2
`
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 6
`
`2.1 Product Information ............................................................................................ 6
`2.2 Tables of Currently Available Treatments for Proposed Indications ................... 6
`2.3 Availability of Proposed Active Ingredient in the United States .......................... 7
`2.4
`Important Safety Issues with Consideration to Related Drugs ............................ 7
`2.5 Summary of Presubmission Regulatory Activity Related to Submission ............ 8
`2.6 Other Relevant Background Information ............................................................ 8
`
`3 ETHICS AND GOOD CLINICAL PRACTICES ......................................................... 8
`
`3.1 Submission Quality and Integrity ........................................................................ 8
`3.2 Compliance with Good Clinical Practices ........................................................... 9
`3.3 Financial Disclosures .......................................................................................... 9
`
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ........................................................................................................... 9
`
`4.1 Chemistry Manufacturing and Controls .............................................................. 9
`4.2 Clinical Microbiology ........................................................................................... 9
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 10
`4.4 Clinical Pharmacology ...................................................................................... 10
`4.4.1 Mechanism of Action .................................................................................. 10
`4.4.2 Pharmacodynamics.................................................................................... 10
`4.4.3 Pharmacokinetics ....................................................................................... 10
`
`5 SOURCES OF CLINICAL DATA............................................................................ 11
`
`5.1 Tables of Studies/Clinical Trials ....................................................................... 11
`5.2 Review Strategy ............................................................................................... 11
`5.3 Discussion of Individual Studies/Clinical Trials ................................................. 11
`5.3.1 Bioavailability and Food Effect Study PR-12111 ........................................... 11
`5.3.2 Oral Irritation Study PR-10007 (Report RR-01708) ....................................... 13
`
`6 REVIEW OF EFFICACY ......................................................................................... 18
`
`Efficacy Summary ...................................................................................................... 18
`6.1
`Indication .......................................................................................................... 19
`6.1.1 Methods ..................................................................................................... 19
`
`7 REVIEW OF SAFETY ............................................................................................. 19
`
`Safety Summary ........................................................................................................ 19
`7.1 Methods ............................................................................................................ 19
`
`Reference ID: 3336601
`
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`

`

` Daniel Davis, MD
`
`Clinical Review NDA 204654
`norethindrone acetate 1 mg/ethinyl estradiol 0.01 mg chewable tablet
`
`
`
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 19
`7.1.2 Categorization of Adverse Events .............................................................. 20
`7.1.3 Pooling of Data Across Studies to Estimate and Compare Incidence ........ 20
`7.2 Adequacy of Safety Assessments .................................................................... 21
`7.2.1 Overall Exposure at Doses/Durations and Demographics ......................... 21
`7.2.2 Explorations for Dose Response ................................................................ 21
`7.2.3 Special Animal and/or In Vitro Testing ....................................................... 21
`7.2.4 Routine Clinical Testing ............................................................................. 21
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 21
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 21
`7.3 Major Safety Results ........................................................................................ 21
`7.3.1 Deaths ........................................................................................................ 21
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 22
`7.3.3 Dropouts and/or Discontinuations .............................................................. 22
`7.4 Supportive Safety Results ................................................................................ 22
`7.4.1 Common Adverse Events .......................................................................... 22
`7.4.2 Laboratory Findings ................................................................................... 23
`7.4.3 Vital Signs .................................................................................................. 23
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 23
`7.4.5 Special Safety Studies/Clinical Trials ......................................................... 23
`7.4.6
`Immunogenicity .......................................................................................... 23
`7.5 Other Safety Explorations ................................................................................. 23
`7.5.1 Dose Dependency for Adverse Events ...................................................... 23
`7.5.2 Time Dependency for Adverse Events ....................................................... 23
`7.5.3 Drug-Demographic Interactions ................................................................. 23
`7.5.4 Drug-Disease Interactions .......................................................................... 24
`7.5.5 Drug-Drug Interactions ............................................................................... 24
`7.6 Additional Safety Evaluations ........................................................................... 24
`7.6.1 Human Carcinogenicity .............................................................................. 24
`7.6.2 Human Reproduction and Pregnancy Data ................................................ 24
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 24
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound ...................... 24
`7.7 Additional Submissions / Safety Issues ............................................................ 24
`7.7.1 4-Month Safety Update and Annual Report ............................................... 24
`
`8 POSTMARKET EXPERIENCE ............................................................................... 25
`
`9 APPENDICES ........................................................................................................ 25
`
`9.1 Literature Review/References .......................................................................... 25
`9.2 Labeling Recommendations ............................................................................. 25
`9.3 Advisory Committee Meeting ............................................................................ 26
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`Reference ID: 3336601
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`

`

` Daniel Davis, MD
`
`Clinical Review NDA 204654
`norethindrone acetate 1 mg/ethinyl estradiol 0.01 mg chewable tablet
`
`
`
`
`
`Table of Tables
`
`Table 1: Summary of Relevant Clinical Studies ............................................................ 11
`Table 2: Visit Schedule for Study 10007 ....................................................................... 15
`Table 3: Demographics in Study 10007 ........................................................................ 16
`Table 4: Number (%) of Subjects with Gingival Irritation and Inflammation ................... 17
`Table 5: Common Adverse Events in Study 10007 (N = 56) ......................................... 18
`
`
`
`List of Abbreviations and Definitions
`
`
`Adverse event
`Body mass index
`Confidence interval
`Combination hormonal contraceptive
`Combination oral contraceptive
`Division of Bone, Reproductive and Urologic Products
`Ethinyl estradiol
`Food and Drug Administration
`Ferrous fumarate
`Good clinical practice
`Norethindrone acetate
`New Drug Application
`Norethindrone
`Oral contraceptive
`Office of Drug Evaluation III
`Office of Scientific Investigation
`Pearl Index
`Serious adverse event
`Venous thromboembolism
`
`AE
`BMI
`CI
`CHC
`COC
`DBRUP
`EE
`FDA
`FF
`GCP
`NETA
`NDA
`NE
`OC
`ODE III
`OSI
`PI
`SAE
`VTE
`
`
`
`
`Reference ID: 3336601
`
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`

`

` Daniel Davis, MD
`
`Clinical Review NDA 204654
`norethindrone acetate 1 mg/ethinyl estradiol 0.01 mg chewable tablet
`
`
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`From a clinical perspective, this reviewer recommends approval of NETA/EE chewable
`tablets containing norethindrone acetate (NETA) 1.0 mg and ethinyl estradiol (EE) 10
`mcg for the Applicant’s proposed indication of “for use by women to prevent pregnancy.”
`The new product will be marketed as a 28-day regimen.
`
`1.2 Risk Benefit Assessment
`
`The risk benefit profile for NETA and EE has been well established for many years and
`the current product contains the same amount and types of active hormones as Lo
`Loestrin Fe, approved on 10-21-10 under NDA 22-501.
`
`The Pearl Index (PI) for Lo Loestrin Fe was derived from the Pregnancy Intent-to-Treat
`Population (PITT), which consisted of all women ages 18-35 who completed at least
`one full cycle of therapy (N=1,270). All 28-day cycles in which subjects used additional
`back-up methods of birth control (including condoms) and all incomplete 28-day cycles
`(except those in which conception occurred) were excluded from the denominator used
`in the PI calculation. A total of 1,270 subjects took the study medication over 12,482
`completed 28-day cycles and 28 pregnancies occurred. The PI was calculated by the
`FDA statistician to be 2.92 (95% CI 1.94, 4.21). The life-table pregnancy rate was
`calculated to be 2.71 (95% CI 1.86, 3.95). The Pearl Index and the life-table analysis
`computations are comparable to those of other approved low dose oral contraceptive
`products and supported the efficacy in preventing pregnancy.
`
`
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`
`No special phase 4 postmarketing studies or risk management steps are recommended.
`The long-term safety of NETA and EE combination products (including Loestrin 24 Fe
`and Loestrin 21 products) has been well established over the past 30 years. There is
`no reason to expect a different safety profile for this new chewable formulation that has
`been shown to be bioequivalent to the marketed Lo Loestrin Fe oral tablets.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`None are recommended.
`
`Reference ID: 3336601
`
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`

`

` Daniel Davis, MD
`
`Clinical Review NDA 204654
`norethindrone acetate 1 mg/ethinyl estradiol 0.01 mg chewable tablet
`
`
`2 Introduction and Regulatory Background
`
`2.1 Product Information
`
`The Applicant is seeking approval of a chewable combination oral contraceptive (COC)
`with the same dosage and regimen as found in the approved product Lo Loestrin Fe.
`The approved product contains the active hormones NETA (1.0 mg) and EE (10 mcg).
`Following 24 days of active hormone use (chewed and swallowed with 240 mL water),
`the patient then takes 2 days of EE 10 mcg tablets (swallowed) and 2 days of ferrous
`fumarate (75 mg) tablets (swallowed).
`
`Reviewer's comment:
`
`1/10 chewable tablet (the
`In this review, the study drug will be referred to either
`name during development) or NETA/EE (the established name, as an acceptable
`tradename has not yet been submitted) and the currently marketed product will be
`referred to as Lo Loestrin Fe. The main benefit for chewable COCs is ease of use for
`patients who have a difficulty swallowing tablets.
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`Contraceptive methods for females include:
` Barrier methods (condom, diaphragm, cervical cap)
` COCs
` Progestin-only oral contraceptives
`Intrauterine devices (levonorgestrel-containing and copper-containing)
`
`
`Injectable contraceptives
` Contraceptive implants
` Contraceptive vaginal rings
` Surgical sterilization (tubal ligation, intratubal obstructive devices)
`
`
`Over the past 40 years there have been several FDA-approved COCs containing
`norethindrone (NE) or NETA and EE on the US market. Many are now generic versions
`of the original products. For example, Loestrin FE 1.5/30 containing 1.5 mg NETA and
`0.030 mg EE was approved in April 1973. Ovcon-50, containing 1 mg NETA and 0.050
`mg EE, was approved under NDA 17-576 on August 28, 1975. Ovcon-35 (0.4 mg
`NETA and 0.035 mg EE tablets) was approved under NDA 17-716 by the FDA on
`March 29, 1976.
`
`For the combination of EE and NETA, the Applicant has the following approved
`products:
`
` Loestrin FE 1.5/30 (EE = 0.03 mg / NETA = 1.5 mg x 21 days, then 7 days
`placebo ferrous fumarate) (NDA 17-355 approved 4-30-73)
`
` Loestrin FE 1/20 (EE = 0.02 mg / NETA = 1.0 mg x 21 days, then 7 days placebo
`ferrous fumarate) (NDA 17-354 approved 4-30-73)
`
`Reference ID: 3336601
`
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`

`

` Daniel Davis, MD
`
`Clinical Review NDA 204654
`norethindrone acetate 1 mg/ethinyl estradiol 0.01 mg chewable tablet
`
`
`
` Loestrin 21 1.5/30 (EE = 0.03 mg / NETA = 1.5 mg. x 21 days, then 7 days
`placebo) (NDA 17-875 approved 10-1-76)
`
` Loestrin 21 1/20 (EE = 0.02 mg / NETA = 1.0 mg x 21 days, then 7 days placebo)
`(NDA 17-876)
`
` Estrostep 21/Fe (EE = 0.02 mg / NETA = 1.0 mg x 5 days, EE = 0.03 mg / NETA
`= 1.0 mg x 7 days, EE = 0.035 mg / NETA = 1.0 mg x 9 days, then 7 days
`placebo ferrous fumarate) (NDA 20-130 approved 10-09-96 and NDA 21-276)
`
` Loestrin 24 FE (EE = 0.02 mg / NETA = 1.0 mg x 24 days and 4 days placebo
`ferrous fumarate) (NDA 21-871 approved 2-17-06)
`
` Lo Loestrin FE (EE = 0.01 mg / NETA = 1.0 mg x 24 days, then 2 days of EE
`0.01 mg, then 2 days of placebo ferrous fumarate) (NDA 22-501 approved 10-
`21-10)
`
` Minastrin 24 Fe soft gel capsules (EE = 0.02 mg / NETA = 1.0 mg x 24 days and
`4 days placebo ferrous fumarate) (NDA 204426 approved 4-19-13)
`
` Chewable Tablets (EE = 0.02 mg / NETA = 1.0 mg x 24 days and 4 days placebo
`ferrous fumarate) (NDA 203667 approved 5-8-13)
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`NETA and EE are readily available and have been since 1968. COCs including the
`aforementioned products are produced by a number of different manufacturers. Most of
`these products are currently available as generics, except for the ones approved in the
`past 2-3 years.
`
`2.4 Important Safety Issues with Consideration to Related Drugs
`
`COCs as a general class have a number of safety issues that have been well-
`recognized since their introduction in the 1960s. The following adverse events represent
`the major concerns described in contraceptive labeling:
`
`
` Vascular events, which may be fatal, including:
`o Deep venous thrombosis (DVT), pulmonary embolism (PE), other venous
`thromboses
`o Myocardial infarction (especially in women >35 years who smoke)
`o Cerebrovascular accidents (CVA): Strokes (both ischemic and
`hemorrhagic types have been reported)
` Hepatic adenomas, hepatic
` Blood pressure increase
` Gallbladder disease
` Headaches
`Irregular uterine bleeding, amenorrhea, oligomenorrhea
`
` Nausea
`
` cholestasis
`
`Reference ID: 3336601
`
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`

`

` Daniel Davis, MD
`
`Clinical Review NDA 204654
`norethindrone acetate 1 mg/ethinyl estradiol 0.01 mg chewable tablet
`
`
`
` Breast tenderness
` Mood changes
` Hypertriglyceridemia
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`There were no presubmission regulatory activities specific to this NDA. Based on prior
`experience and similar submissions to the Division (NDA 21-490, Ovcon chewable
`tablet, approved on November 14, 2003;
`24 Fe chewable tablet,
`; NDA 203667,
`approved on May 8, 2013), the Applicant was aware of the studies needed for approval
`of a different formulation of an approved COC. The Division recommended to the
`Applicant at a previous meeting concerning a
`that an oral irritation study would be required. There was also discussion relating to
`
`
`
`
`
`
`
`
`
`2.6 Other Relevant Background Information
`
`The proposed regimen, and consequently the exposure to NETA and EE, is the same
`as the approved regimen for Warner Chilcott’s Lo Loestrin 24 Fe (NETA and EE tablets
`USP and ferrous fumarate tablets) which received approval as an oral contraceptive on
`October 21, 2010 under NDA 022501. The application contains results of Study PR-
`12111 (Report RR-04612), which show that
` 1/10 chewable tablets are
`bioequivalent to Lo Loestrin Fe tablets and can be taken without regard to meals.
`
`The same 10 mcg EE tablets, referred to in this NDA as WC3016 EE10 tablets, that are
`used in Lo Loestrin Fe will be used for the administration of 10 mcg EE over two days
`(Days 25-26) and swallowed (not chewed). This is reflected in the proposed container
`labeling and proposed labeling text. Although the application provides results of Study
`PR-12011 (Report RR-04512) which compared the bioavailability of
`EE10
`chewable tablets chewed to WC3016 EE10 tablets swallowed, it should be noted that
`the EE10 chewable tablets are not proposed for the to-be-marketed product. Results of
`Study PR-12011 are included by the Sponsor only in order to provide complete safety
`information for this NDA submission.
`
`3 Ethics and Good Clinical Practices
`
`3.1 Submission Quality and Integrity
`
`There are no issues concerning the quality and integrity of the submission and the
`studies submitted with this NDA. The Office of Scientific Investigations (OSI) made
`inspections of the clinical and bioanalytical study sites for the clinical pharmacology
`studies and found no significant deficiencies.
`
`Reference ID: 3336601
`
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

` Daniel Davis, MD
`
`Clinical Review NDA 204654
`norethindrone acetate 1 mg/ethinyl estradiol 0.01 mg chewable tablet
`
`
`3.2 Compliance with Good Clinical Practices
`
`The submission quality and compliance of the clinical study 10007 (oral irritability)
`appears acceptable. The clinical pharmacology studies were in compliance with Good
`Clinical Practices (GPC) and appropriate consent forms were signed.
`
`3.3 Financial Disclosures
`
`All investigators who participated in Studies PR-12011, PR-12111 and PR-10007
`certified to not having a financial interest. In addition, all investigators who participated
`in Studies PR-14106 and PR-14206 previously conducted in support of NDA 22-501 for
`Lo Loestrin Fe also certified to not having a financial interest. Therefore, there are no
`financial disclosures that need reviewing.
`
`4 Significant Efficacy/Safety Issues Related to Other Review
`Disciplines
`
`4.1 Chemistry Manufacturing and Controls
`
`1/10 chewable tablet formulation was based on the approved formulation
`The
`for Lo Loestrin Fe 1 mg NETA/10 mcg EE tablets (referred to in the NDA as WC3016
`1/10 tablets or by its formulation WC3016-21C tablets); a flavor and sweetener were
`added to
` 1/10 chewable tablets. The WC3016 EE10 tablets are identical to
`the marketed Lo Loestrin Fe 10 mcg EE tablets. The drug product is provided in a
` blister pack. The chewable combination tablets are
`contained in the first 24 wells of the blister pack, while the nonchewable EE tablets are
`contained in blister wells 25-26 and the inert, nonchewable FF tablets are in blister wells
`27-28. The blister packaging is the same as used in the approved product under NDA
`22501.
`
`The FDA chemist Gene Holbert, PhD reviewed the data and concluded on 6-18-13 from
`the ONDQA perspective that:
`
`“The applicant of this NDA has provided sufficient CMC information to assure the
`identity, strength, purity, and quality of the drug product.”
`
`In his review he did note that:
` The Office of Compliance has not issued an overall “Acceptable” recommendation
`for the facilities involved in the NDA as of the date of this review.
` Labels/labeling issues have not yet been resolved.
`
`4.2 Clinical Microbiology
`
`There is no clinical microbiology report because it is not required for this oral tablet.
`
`Reference ID: 3336601
`
`9
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`(b) (4)
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`(b) (4)
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`

`

` Daniel Davis, MD
`
`Clinical Review NDA 204654
`norethindrone acetate 1 mg/ethinyl estradiol 0.01 mg chewable tablet
`
`
`4.3 Preclinical Pharmacology/Toxicology
`
`The preclinical review was done by Krishan Raheja, PhD, and completed on 4-19-13.
`Both NETA and EE are synthetic hormones that are widely used as components of both
`COCs and hormone replacement therapy. Also, the daily doses of NETA and EE
`proposed in the present application are found in currently approved COCs. The inactive
`ingredients used in the 24 active tablets, EE tablets, and in the ferrous fumarate tablets
`are compendial or Generally Recognized as Safe (GRAS) and are listed in the FDA’s
`Inactive Ingredients Database. Dr. Raheja concludes: “Pharmacology/Toxicology
`recommends approval o
` under NDA 204654 for the indication of prevention of
`pregnancy.”
`
`Reviewer’s comment:
`
`I concur with Dr. Raheja’s recommendation.
`
`4.4 Clinical Pharmacology
`
`Li Li, Ph.D. had the following recommendation in her primary review dated June 20,
`2013:
` “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”.
`
`4.4.1 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.
`
`4.4.2 Pharmacodynamics
`
`No specific pharmacodynamic studies were conducted for this NDA submission.
`
`4.4.3 Pharmacokinetics
`
`In Study PR-12111 it was shown that the to-be-marketed chewable tablets are
`bioequivalent to the active combination Lo Loestrin Fe tablets.
`
`Reviewer’s comment:
`
`On 6-20-13, the clinical pharmacology review was completed by Li Li, PhD. Her
`recommendation follows:
`
`“The Office of Clinical Pharmacology (OCP)/Division of Clinical Pharmacology 3 (DCP-3)
`has reviewed NDA 204426 submitted on June 21, 2012, September 11, 2012, and
`September 27, 2012. The overall Clinical Pharmacology information submitted to support
`this NDA is acceptable provided that a satisfactory agreement is reached regarding the
`labeling language.”
`
`Reference ID: 3336601
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`

`

` Daniel Davis, MD
`
`Clinical Review NDA 204654
`norethindrone acetate 1 mg/ethinyl estradiol 0.01 mg chewable tablet
`
`
`
` concur with her recommendation.
`
` I
`
`5 Sources of Clinical Data
`
`5.1 Tables of Studies/Clinical Trials
`
`Only two clinical studies are relevant to the approval of this NDA submission. Study
`PR-12111 evaluated the bioavailability and food effect of the chewable
` tablet
`and the reference tablet WC3016 containing the combination of NETA and EE. The oral
`safety study (PR-10007) assessed the potential for oral irritation when tablets containing
`a higher dose of 1 mg NETA and 20 mcg EE are chewed daily for 24 days.
`
`Table 1: Summary of Relevant Clinical Studies
`
`Study
`
`Objective
`
`Design
`
`PR-12111
`
`Bioavailability
`and food effect
`
`3-way cross-
`over; single dose
`single center
`
`Enrolled/
`
`Completed
`
`42/40
`
`PR-10007
`
`Oral irritation and
`safety
`
`Open-label,
`single center
`
`56/52
`
`Source: modified from Sponsor’s Tabular Listing of All Clinical Studies.
`
`5.2 Review Strategy
`
`Clinical
`comment
`
`Studied only the
`NETA/EE
`chewable tablet
`
`Studied higher
`dose NETA/EE
`
`Because this NDA is a request to approve a different formulation of an approved COC
`product, the primary requirement is to demonstrate bioequivalence to the reference
`drug. Most important for the approval are the clinical pharmacology and CMC reviews.
`All disciplines will review the label to make sure it is complete and accurate.
`
`The clinical review will assess following:
` Oral irritability study
` Safety findings from the clinical pharmacology studies
` 4-month safety update
` Postmarketing safety review and Annual Report for Lo Loestrin Fe
`
`5.3 Discussion of Individual Studies/Clinical Trials
`
`5.3.1 Bioavailability and Food Effect Study PR-12111
`
`The chewable tablet formulation has added mint flavor and sweetener with a
`corresponding reduction in the amount of mannitol. There is one clinical pharmacology
`study that is critical to the approval of this NDA application. Study PR-12111 (Report
`
`Reference ID: 3336601
`
`11
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`

`

` Daniel Davis, MD
`
`Clinical Review NDA 204654
`norethindrone acetate 1 mg/ethinyl estradiol 0.01 mg chewable tablet
`
`
` 1/10 chewable tablets to approved and
`RR-04612) was conducted to compare
`marketed WC3016 1/10 tablets and to assess the effect of food on the bioavailability of
`NETA and EE from the 1/10 chewable tablets in healthy female volunteers (median age
`35; range 20−45 years). This single-center, randomized, balanced, single-dose, 3-
`treatment, 3-period, 6-sequence, crossover, comparative bioavailability/food effect study
`was conducted under medical supervision. Subjects were randomly assigned to receive
`one of the following 3 treatments in each of 3 treatment periods:
`
`• Treatment A: WC3016 1/10 tablet orally administered under fasted conditions
`
`• Treatment B:
`conditions
`
`1/10 chewable tablet orally administered under fasted
`
` 1/10 chewable tablet orally administered with food
`
`• Treatment C:
`
`All tablets were administered with about 240 mL ambient-temperature water. Treatment
`periods were separated by at least 7 days. Forty-two (42) subjects were dosed, 40
`subjects completed all 3 treatment periods, and 38 were evaluable for pharmacokinetic
`analysis.
`
`1/10 chewable tablets were generally well-tolerated.
`WC3016 1/10 tablets and
`The chewable tablets were demonstrated to be bioequivalent to WC3016 1/10 tablets
`(Lo Loestrin Fe).
`
` 1/10 chewable tablets were administered with food, the rate of NETA
`When
`and EE absorption was decreased and Cmax values were decreased by 46% for NETA
`and 41% for EE. However, the AUC values for the extent of NETA and EE absorption
`were not significantly different. The Sponsor concluded that the food effect is not
`clinically significant and that the 1/10 chewable tablets can be chewed and swallowed or
`swallowed whole.
`
`Reviewer’s comment:
`
`It should be noted that the clinical pharmacology team did not agree that the dosing
`instructions for the WC3016 tablet can allow an option that the tablet could also be
`swallowed whole. The bioavailability study specifically did not test the chewable tablet
`swallowed whole. The approved label will state that the 24 chewable blue tablets should
`be chewed, swallowed, and then followed immediately by a full glass (8 ounces) of water.
`This was the same procedure that was used in the study.
`
`For a detailed analysis of this studies regarding study design and clinical results, see the
`Clinical Pharmacology review by Li Li, PhD.
`
`There were no safety issues seen with this study which involved 42 subjects taking only
`3 single tablets separated by at least 7 days.
`
`For this pivotal BE study, a formal consult to the Office of Scientific Investigations (OSI)
`was made on 1-18-13 for inspections of the clinical and bioanalytical study sites. There
`were no significant objectionable issues identified in the clinical site of the BE study and
`Form FDA-483 was not issued. Following inspection on the analytical site in
`
`
`Reference ID: 3336601
`
`12
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

` Daniel Davis, MD
`
`Clinical Review NDA 204654
`norethindrone acetate 1 mg/ethinyl estradiol 0.01 mg chewable tablet
`
`
`
` Form FDA-483 was issued on 4-19-13 based
`on the following observation: “Not all aspects of study conduct were documented. For
`example: failure to maintain documentation for individual QC sets used during sample
`processing.”
`
` A
`
` to the inspectional findings was received on May 14,
` written response from
`2013. Dr. Adrindam Dasgupta’s OSI consult review, dated 5-30-13 in DARRTS, states
`the following conclusion:
`Following review and evaluation of the Form FDA-483 observation and response
`from the analytical site, in my opinion, the clinical and analytical data generated
`for study PR-12111 were not affected by the cited deficiency. I recommend that
`the data for clinical and analytical portion of study PR-12111 be accepted for
`further agency review.
`
`Reviewer’s comment:
`
`On 6-4-13, Dr. Dasgupta clarified that the “data be accepted for further agency review”
`meant the data was acceptable for further review by the clinical reviewer (medical officer)
`and clinical pharmacology reviewer. The OSI review found the data from the clinical and
`bioanalytical sites to be acceptable.
`
`Discussion of the safety data from this study is included in the review of pooled safety
`data in Section 7.3.
`
`5.3.2 Oral Irritation Study PR-10007 (Report RR-01708)
`
`Reviewer’s comment:
`
`1/10 chewable tablets when chewed, the
`In order to support the oral safety of
`NDA submission contains the results of Study PR-10007 (Report RR-01708), which
`assessed the potential for oral irritation when tablets containing 1 mg NETA and the
`higher dose of 20 mcg EE are chewed and then swallowed for 24 consecutive days. The
`review in this Section 5.3.2 was done by Jerry Willett, MD as part of the NDA 203667
`clinical review for a new chewable formulation of
` 24 Fe. Dr. Willett’s review
`focuses on the clinical safety analysis and safety results in this section.
`
`5.3.2.1 Title
`
`“A Clinical Study to Evaluate the Safety of Loestrin Oral Contraceptive Following Daily
`Use by Human Female Subjects”
`
`5.3.2.2 Study Objective
`
`The