CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`204654Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`Cross Discipline Team Leader Review
`NDA 204-654 Lo Minaslrin Fe
`7/24/13 FINAL
`
`Cross-Discipline Team Leader Review
`
`Jul 24, 2013
`
`Lisa M. Soule, M.D.
`From
`
`Subject
`Cross—Discipline Team Leader Review
`NDA/BLA #
`204-654
`
`Warner Chilcott Coman , LLC
`A licant
`
`Date of Submission
`September 28, 2012
`PDUFA Goal Date
`Jul 28, 2013
`
`Proprietary Name /
`Established (USAN) names
`
`Lo Minastrin Fe
`Ethinyl estradiol (EE)/Norethindrone acetate (NETA), EE
`alone, and ferrous fumarate FF tablets
`EB 10 ug/NETA 1 mg chewable tablet and EB 10 ug
`Dosage forms / Strength
`
`tablet to be swallowed
`
`A ; roval
`
`Dose Regimen
`
`l EE/NETA chewable tablet daily for 24 days, followed
`by 2 days of EE—alone (swallowed) and 2 days of FF
`
`Pro nosed Indication 5
`Recommended:
`
`Prevention of re m anc
`
`1.
`
`Introduction
`
`This NDA seeks approval for a chewable combination oral contraceptive (COC) containing
`norethindrone acetate (NETA) and ethinyl estradiol (EE); the COC is intended to be
`bioequivalent (BE) to the COC Lo Loestrin Fe, approved under NDA 22-501. The dose
`regimen is the same as that for L0 LoestIin Fe aside from chewing the combination tablets,
`and consists of :
`
`0 Days 1-24: one mint-flavored combination EE/NETA tablet (chewed)
`
`0 Days 25-26: one 10 ug EE-alone tablet (swallowed)
`
`0 Days 27-28: one inactive tablet containing ferrous fumarate (FF, swallowed).
`
`Tablets may be taken without regard to meals.
`
`There are several approved NDAs for chewable COCs; those currently marketed are Femcon
`Fe (NDA 21—490) and Generess Fe (NDA 22-573).
`
`2. Background
`2.1
`DESCRIPTION OF PRODUCT
`
`NETA and EE are well-characterized progestin and estrogen products, respectively, that are
`widely used in combined hormonal contraceptive products. These products reduce the risk of
`pregnancy mamly via the effect of the progestin on suppressing ovulation, along with
`changes in cervical mucus that inhibit sperm motility and endometrial changes that may
`inhibit implantation. The estrogen component may make some contribution to the
`contraceptive action, and mainly acts to maintain cycle control and provide an acceptable
`bleeding profile.
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`Reference ID: 334631 3
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`Cross Discipline Team Leader Review
`NDA 204-654 Lo Minaslrin Fe
`7/24/13 FINAL
`
`The Applicant has several approved COC products that contain EE and NETA. The Loestrin
`family of products had its initial approval in 1976, and includes Loestrin products containing
`30 pg EE/ 1.5 mg NETA or 20 pg EE/l mg NETA administered in a 21/7 regimen; Loestrin
`24 Fe, which contains 20 pg EE/l mg NETA and is administered in a 24/4 day regimen with
`four days of FF, and Lo Loestrin Fe, which contains 10 pg EE/l mg NETA and is
`administered in a 24/2/2 day regimen with two days of EE-alone and two days of FF. Lo
`Loestrin Fe contains the lowest EE dose in any approved COC, and is the reference drug for
`the current chewable tablet.
`
`Of the chewable fonnulations (most manufactured by another sponsor), Femcon Fe was
`approved in 2003 and contains 35 pg EE/400 pg NETA administered in a regimen of 21 days
`of active combination tablets and 7 days of FF tablets. A lower dose version, Generess, was
`approved in 2010; it contains 25 pg EE/800 pg NETA, and is administered in the same
`regimen as Femcon Fe. Another Warner Chilcott chewable product, BE to Loestrin 24 Fe,
`was approved under NDA 203—667 in May 2013 and has not yet been marketed. A capsule
`bioequivalent to Loestrin 24 Fe was also approved, under NDA 204—426, in April 2013 and
`has not yet been marketed.
`
`2.2
`
`REGULATORY HISTORY
`
`Because the Applicant had experience developing chewable formulations of approved COC
`products, it understood the Division’s requirements for approval of such a formulation (e.g.,
`conduct of an oral irritation study) and did not request advice during the development
`program for this product.
`
`2.3
`
`PRIMARY MEDICAL REVIEWER’S RECOMMENDATION FOR
`
`APPROVABILITY
`
`The primary reviewer, Dr. Daniel Davis, stated in his review dated July 5, 2013:
`
`From a clinicalperspective, this reviewer recommends approval ofNETA/EE chewable
`tablets containing norethindrone ACETA TE (NETA) 1 mg and ethinyl estradiol (EE) 10
`mcgfor the Applicant’s s proposed indication of ‘for use by women to prevent
`pregnancy. " The new product will be marketed as a 28-day regimen.
`
`Team Leader Comment:
`
`I concur with Dr. Davis’ recommendation.
`
`Dr. Davis did not recommend any postmarketing risk evaluation and mitigation strategies or
`postmarketing requirements/commitments.
`
`3. CMCIDevice
`
`3.1
`
`CMC
`
`A USP monograph about the combination of the drug substances (EE and NETA) has been
`published. Information about each drug substance from its respective manufacturer is
`contained in drug master files (DlVIFs), which have been reviewed several times and
`determined to be adequate. The primary Chemistry Reviewer, Gene Holbert, Ph.D., noted
`that the formulation of the chewable combination tablets
`(mg) is based on the
`previously approved formulation in NDA 22—501, with the difference being that the current
`tablet is chewable. The formulations are identical except for
`M0
`Dissolution
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`Reference ID: 3346313
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`Cross Discipline Team Leader Review
`NDA 204-654 Lo Minastrin Fe
`7/24/13 FINAL
`
`data confirm that the release of NETA and EE are similar for both formulations. The EE-
`alone and FF tablets are identical to those approved in NDA 22-501.
`Dr. Holbert found the analytic methods to be appropriately validated. Expiry of 12 months
`was proposed by the Applicant based on six month data for the combination tablets at the
`long-term and intermediate conditions and extrapolation of the long-term data; this was
`acceptable. The expiry will be amended as results of ongoing stability testing become
`available.
`Dr. Holbert provided labeling recommendations that were conveyed to the Applicant; carton
`and container labeling were acceptable. Five manufacturing and testing sites were found
`acceptable on profile and one based on district recommendation. One drug substance
`manufacturer
` was scheduled for inspection and one had been inspected but no
`recommendation made at the time of his review.
`At the time of Dr. Holbert’s review, labeling negotiations had not been completed and the
`overall recommendation by the Office of Compliance was pending; therefore, he made the
`following recommendations in his review dated June 18, 2013:
`The applicant has provided sufficient information to assure the identity, strength,
`purity, and quality of the drug product.
`The Office of Compliance has not issued made 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.
`Therefore, from the ONDQA perspective, this NDA is not recommended for
`approval per 21 CFR 314.125(b)(1), (13) until the issues delineated above are
`satisfactorily resolved.
`No post-marketing commitments or risk management strategies were recommended.
`Following submission of acceptable labeling, Dr. Holbert submitted an addendum to his
`review on July 23, 2013, noting that CMC-related labeling issues had been resolved and
`carton/container labeling was acceptable. The Office of Compliance issues an overall
`“Acceptable” recommendation on July 9, 2013. He made the following recommendation:
`This NDA is now recommended for Approval from the ONDQA perspective with an
`expiration dating period of 12 months.
`4. Nonclinical Pharmacology/Toxicology
`The Applicant did not conduct any preclinical studies for this NDA, but referenced the NDA
`for its existing Lo Loestrin Fe product (22-501) to fulfill the requirements for nonclinical
`evaluation. The active ingredients are the same as those in the NDA 22-501, while the
`inactive ingredients are either compendial or Generally Recognized as Safe and are at or
`below the quantities listed in the FDA Inactive Ingredient Database for a chewable or oral
`tablet.
`The primary Toxicology Reviewer, Krishan Raheja, D.V.M., Ph.D., made the following
`recommendations in his NDA review dated April 19, 2013:
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`Reference ID: 3346313
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`(b) (4)
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`Cross Discipline Team Leader Review
`NDA 204-654 Lo Minastrin Fe
`7/24/13 FINAL
`
`
`Recommendations on approvability: Pharmacology/Toxicology recommends approved
`of
` under NDA 204654 for the indication of prevention of pregnancy.
`Additional Non Clinical Recommendations: None
`Recommendations on labeling: Sponsor has provided drug label in PLR format which is
`acceptable from the Pharmacology/Toxicology perspective.
`5. Clinical Pharmacology/Pharmacometrics
`5.1
`Clinical Pharmacology
`The Applicant submitted a bioequivalence (BE) study, Study PR-12111 to demonstrate that
`the chewable combination tablets in this NDA (known as
`1/10 tablets) are
`bioequivalent to the combination tablets taken by swallowing with water in the approved
`product Lo Loestrin Fe. The EE-alone and FF tablets are identical to those used in Lo
`Loestrin so no demonstration of bioequivalence was needed for those tablets. Study PR-
`12111 also evaluated the effect of food on the bioavailability of NETA and EE from the
`1/10 tablets.
`The primary Clinical Pharmacology Reviewer, Li Li, Ph.D., concluded that the NETA and
`EE exposure with
` 1/10 tablets was bioequivalent to that obtained with the
`combination tablets from Lo Loestrin Fe. The 90% confidence intervals for the test:reference
`ratio for Cmax, AUC0-t and AUC 0-inf were within the 80-125% limit for both NETA and
`EE when both drugs were administered under fasting conditions. When the bioavailability of
`1/10 tablets were compared for fasting and fed conditions (a high fat meal), the fed
`condition reduced the rate (Tmax), but not the extent of NETA and EE absorption. However,
`1/10 tablets administered under fed conditions remained bioequivalent to Lo
`Loestrin Fe tablets (fasting).
`No new drug interaction studies were conducted, nor were studies done to evaluate the
`impact of renal or hepatic impairment. Information from Lo Loestrin Fe labeling will be
`provided in the labeling for this chewable product.
`Dr. Li stated the following in her 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..
`Dr. Li did not recommend any phase 4 requirements or commitments.
`Following submission of acceptable labeling, Dr. Li submitted an addendum to her review on
`July 24, 2013, noting that labeling issues had been resolved and the final labeling was
`acceptable. She made the following recommendation:
`The Division of Clinical Pharmacology-3, Office of Clinical Pharmacology finds
`the NDA 204654 acceptable .
`6. Clinical Microbiology
`No clinical microbiology consult was requested for this oral tablet product.
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`Cross Discipline Team Leader Review
`NDA 204-654 Lo Minastrin Fe
`7/24/13 FINAL
`
`7. Clinical/Statistical – Efficacy
`No new efficacy data was submitted in this NDA; findings of efficacy for NDA 22-501 were
`bridged through the demonstration of bioequivalence of this chewable combination tablet to
`the non-chewable tablet in that NDA. The approval of NDA 22-501 was based on a single
`13-cycle open label clinical trial that enrolled over 1,600 women and demonstrated a Pearl
`Index of 2.92 (95% confidence interval [CI] of 1.9-4.2). While this Pearl Index was higher
`than that for any previously approved COC, the 95% CI were within the range of other
`approved products. This trial excluded women with a body mass index (BMI) above 35
`kg/m2, and due to concerns about the already-high Pearl Index coupled with lack of data on
`efficacy in obese women, the Division determined that labeling should include a statement
`that safety and efficacy in women with BMI > 35 have not been determined.
`Team Leader Comment:
`The labeling for this chewable tablet should also contain the BMI statements found in
`Lo Loestrin Fe.
`Xin Fang, Ph.D., the statistical reviewer, noted that no new efficacy data were provided in
`the current NDA and therefore, no statistical review was needed.
`8. Safety
`The safety database is based on results from Study PR-12111, the pivotal BE study that
`enrolled 42 healthy volunteers in a three-period, single dose cross-over design, and Study
`PR-10007, the oral irritation study that enrolled 56 women for a 24-day treatment period.
`Team Leader Comment:
`Given the safety database for NDA 22-501, the extent of exposure in this NDA is
`acceptable.
`Deaths
`There were no deaths in the clinical development program.
`Serious Adverse Events
`There were no serious adverse events in either study.
`AEs leading to Discontinuation
`A single subject in Study PR-12111 withdrew due to a mild headache and mild vomiting
`within the first two hours after dosing with
`with food. There were no AEs leading
`to discontinuation in Study PR-10007.
`Common AEs
`In Study PR-12111, 15 subjects who received the chewable tablet reported AEs (14.6% of
`those who received the tablet under fasted conditions and 21.4% who received it under fed
`conditions. Headache was the only AE that occurred in more than one subject.
`In Study PR-10007, 21.4% of subjects reported a non-oral-soft-tissue AE (oral irritation is
`discussed in Section 8.1. AEs were typically respiratory infectious conditions; potential ARs
`included two cases of tooth fracture and one of tachycardia. The tooth fractures were
`unrelated to study drug; one occurred while eating chewy candy and one subject chipped a
`crown while eating an orange two days after dosing had been completed. The case of
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`Cross Discipline Team Leader Review
`NDA 204-654 Lo Minastrin Fe
`7/24/13 FINAL
`
`tachycardia occurred after dosing had been completed and responded to oxygen; a work-up
`in the Emergency Department was negative.
`Laboratory Testing and Vital Signs
`There were no signals of concern in either study.
`8.1
`ORAL IRRITATION STUDY
`Study PR-10007 was conducted using chewable tablets consisting of NETA 1 mg/EE 20 µg
`administered for 24 days, and was reviewed under NDA 203-667 by Dr. Gerald Willett.
`Because this study was conducted using a higher dose tablet, it was determined that it would
`also provide relevant oral safety data for this NDA.
`Oral soft tissue examinations were multiple times during the treatment period, and subjects
`were scored for irritation/inflammation and for abrasions. Dr. Willet noted that the only site
`with notable inflammation (albeit scored only as erythema plus slight edema, the lowest non-
`0 score) was the gingiva, and these findings actually improved from screening. There were
`no oral abrasions reported. Dr. Willett concluded that there were no clinically significant
`safety findings in this study.
`8.2
`POSTMARKETING SAFETY FINDINGS
`The current chewable product has not been approved for marketing anywhere in the world,
`so there are no postmarketing safety data on this product. However, safety information has
`been submitted regularly on the related Lo Loestrin Fe product, and this was reviewed. A
`915 review was conducted in September 2012 and noted reports of VTEs (four pulmonary
`emboli and two deep vein thromboses). Although the risk of VTE is described in COC class
`labeling, because this product (like Lo Loestrin Fe) contains a particularly low dose of EE,
`which might be perceived as safer than higher-dose COCs, these reports should be noted in
`the Adverse Reactions section of labeling.
`8.3
`SAFETY UPDATE
`A 120-day Safety Update was submitted on January 23, 2013, and consisted of updated Lo
`Loestrin Fe postmarketing safety data. There were no new or ongoing studies with the
`chewable tablet. No new safety findings or concerns were identified by the Applicant.
`Team Leader Comment:
`I concur that there is no new safety concern based on the Safety Update.
`8.4
`OVERALL ASSESSMENT OF SAFETY FINDINGS
`The reference swallowed product, Lo Loestrin Fe, has been approved since late 2010, and no
`new or unexpected safety signals have been identified in postmarketing surveillance or in the
`915 review done last fall. There is no reason to anticipate a different safety profile for this
`chewable version. The limited clinical trials submitted in support of this NDA did not reveal
`any safety concerns, and the oral irritation study did not demonstrate any adverse findings of
`concern.
`9. Advisory Committee Meeting
`An Advisory Committee meeting was not requested for this application, as it does not utilize
`a novel combination of contraceptive hormones or dose regimen, and it is not the first
`chewable COC marketed.
`
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`Cross Discipline Team Leader Review
`NDA 204-654 Lo Minastrin Fe
`7/24/13 FINAL
`
`10. Pediatrics
`The Applicant requested a full waiver of the requirement for pediatric studies. However, the
`change to a chewable formulation did not trigger PREA; therefore, no pediatric studies were
`required for this application.
`11. Other Relevant Regulatory Issues
`The Applicant certified that it did not use any debarred investigators. The Applicant certified
`that none of the investigators in Studies PR-12111 or PR-10007 had any financial
`disclosures.
`The Office of Scientific Investigation (OSI) inspected the clinical and analytic sites for Study
`PR-12111. The inspection at the clinical site revealed no deficiencies and no Form FDA-483
`was issued. Following the inspection at the analytical site in
`a Form FDA-483 was
`issued, and a written response was provided by the facility. The observation of concern was
`that the site failed to maintain documentation for individual quality control sets (i.e., identity
`of the spiking solutions used in pre-study qualification runs). The OSI inspector noted that
`evaluation of quality control stability and accuracy was also made during the actual study and
`confirmed the results obtained during the pre-study qualification.
`Arindam Dasgupta, Ph.D. from OSI made the following overall assessment and general
`recommendations in his review dated May 30, 2013:
`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.
`12. Labeling
` which was found to be
`The Applicant submitted the proposed proprietary name
`unacceptable by the Division of Medication Error Prevention and Analysis (DMEPA). On
`June 27, 2013, the Applicant requested review of the proprietary name Lo Minastrin Fe, and
`this was found acceptable by DMEPA.
`Final carton and container labeling was submitted on July 16, 2013 and was found acceptable
`by the DMEPA and CMC reviewers. The label was submitted in the format prescribed by
`the Physician Labeling Rule (PLR), and was revised in accord with current class labeling for
`COCs. Input from DMEPA, the Study Endpoints and Labeling Development (SEALD) team
`and the Office of Prescription Drug Promotion (OPDP) was incorporated in labeling
`revisions. Agreement on labeling was reached with the Applicant on July 24, 2013.
`13. Recommendations/Risk Benefit Assessment
`13.1
`Recommended Regulatory Action
`I recommend that this NDA receive an Approval action.
`
`Page 7 of 8
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`Reference ID: 3346313
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`(b) (4)
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`(b) (4)
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`Cross Discipline Team Leader Review
`NDA 204-654 Lo Minastrin Fe
`7/24/13 FINAL
`
`
`Risk Benefit Assessment
`13.2
`By demonstrating bioequivalence with the approved COC Lo Loestrin Fe, the Applicant has
`successfully bridged the current proposed chewable formulation to the previous findings of
`safety and efficacy for Lo Loestrin Fe. The safety profile in the two studies conducted in
`support of this NDA does not reveal any new or unexpected safety signals. The overall
`risk/benefit profile is acceptable.
`13.3
`Recommendation for Postmarketing Risk Management Activities
`None
`13.4
`
`Recommendation for other Postmarketing Study Requirements
`and Commitments
`
`Recommended Comments to Applicant
`
`None
`13.5
`None
`
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`Reference ID: 3346313
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`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LISA M SOULE
`07/24/2013
`
`AUDREY L GASSMAN
`07/24/2013
`
`Reference ID: 3346313
`
`