CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`022501Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`
`
`NDA: 22-501
`
`Brand Name
`Generic Name
`
`Reviewer
`Team Leader
`OCP Division
`OND Division
`Sponsor
`Submission Type
`Formulation; Strength(s)
`
`Indication
`
`
`Table of Contents
`
`Submission Date(s): 04/20/2010 (Resubmission)
`03/26/2009; 12/23/2009 (Original)
`Lo Loestrin Fe®
`WC3016 (norethindrone acetate, NA 1 mg and
`ethinyl estradiol, EE 10 µg tablets, ethinyl estradiol
`10 µg tablets and ferrous fumarate tablets)
`Sandhya Apparaju, Ph.D.
`Myong Jin Kim, Pharm.D.
`Division of Clinical Pharmacology III (DCP3)
`Division of Reproductive and Urologic products
`Warner Chilcott
`NDA Resubmission
`Oral tablets; 1 mg /10 µg NA/EE tablets and 10 µg
`EE alone tablets
`Prevention of pregnancy
`
` Executive Summary ..................................................................................................... 2
`1.1 Recommendation................................................................................................... 2
`
`1
`
` 1
`
`
`
`
`
`

`

`Executive Summary
`
`1
`
`The original NDA for WC3016 tablets for prevention of pregnancy (NDA 22-501) was
`submitted on March 26, 2009. The subject of the NDA is a low dose oral contraceptive
`consisting of 10 µg of EE and 1 mg of NA (WC3016 1/10 tablets) taken once daily for 24
`days, followed by two daily doses of 10 µg of EE (WC3016 EE10 tablets) and ferrous
`fumarate tablets (75 mg) for 2 days during a 28-day regimen. Three Clinical
`Pharmacology studies and one phase 3 safety and efficacy trial were conducted in support
`of this NDA.
`An optional intra-divisional Clinical Pharmacology briefing was held for this NDA on
`November 16, 2009. NDA was found acceptable from a Clinical Pharmacology
`perspective provided an agreement could be reached with the sponsor pertaining to
`labeling language [refer to Clinical Pharmacology review in DARRTS signed on
`11/27/2009].
`During the first review cycle the NDA received a complete response action (letter dated
`January 26, 2010) due to pending CMC issues (deficiencies identified during inspections
`of the drug substance manufacturing facility and a control testing laboratory).
`Satisfactory resolution of these deficiencies was required before the application could be
`approved. Labeling was not finalized at the time of complete response action.
`With this NDA resubmission (submitted 04/20/2010), sponsor intends to address the
`unresolved deficiencies noted in the first cycle. In addition, draft labeling that
`incorporates edits recommended by the Division during the first review cycle has also
`been included for review.
`
`Labeling review: On December 23, 2009 during the first NDA review cycle, sponsor
`submitted revised draft labeling and additional information in response to labeling
`comments sent by the Division via e-mail on December 15, 2009. The sponsor had at the
`time accepted most of the recommended labeling changes including Clinical
`Pharmacology changes to Drug Interactions (7.0), Use in Specific Populations (8.0), and
`Clinical Pharmacology (12.0). In addition, the sponsor provided further justification to
`support a labeling statement pertaining to metabolic conversion of NA to EE within this
`section.
`Following review of the sponsor’s December 23, 2009 response to labeling edits,
`additional labeling comments were sent to the sponsor with the second round of labeling
`edits in January 2010. In the NDA resubmission, sponsor has adequately addressed
`pending labeling comments. In addition, Minor revisions to the Clinical Pharmacology
`sections of the proposed draft labeling were recommended during the review of the
`resubmitted labeling and were accepted by the sponsor. There are no pending Clinical
`Pharmacology issues with regard to the proposed labeling.
`
`
`1.1 Recommendation
`NDA 22-501 is acceptable from a Clinical Pharmacology perspective.
`
`
`
`2
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SANDHYA K APPARAJU
`10/07/2010
`
`MYONG JIN KIM
`10/12/2010
`
`Reference ID: 2847190
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`
`
`NDA: 22-501
`Brand Name
`Generic Name
`
`Reviewer
`Team Leader
`OCP Division
`OND Division
`Sponsor
`Relevant IND(s)
`Submission Type; Code
`Formulation; Strength(s)
`
`Submission Date: 03/26/2009
`
`Norethindrone acetate (NA) & Ethinyl Estradiol
`(EE) tablets, and Ferrous Fumarate tablets
`Sandhya Apparaju, Ph.D.
`Myong Jin Kim, Pharm.D.
`Division of Clinical Pharmacology 3
`Division of Reproductive and Urologic Products
`Warner Chilcott, LLC
`73,510
`Original NDA
`Oral immediate release tablets; 1 mg NA + 10 µg
`EE, 10 µg EE, Ferrous Fumarate 75 mg
`Prevention of Pregnancy
`Indication
`An optional intra-division level OCP briefing was held for NDA 22-501 on Monday, 16 November, 2009 from 1- 2 PM
`in WO Bldg 51 Conference Room 3200. Attendees included Dr’s. Hae Young Ahn, Myong Jin Kim, Ron Orleans,
`Darrell Abernathy, Hyunjin Kim, LaiMing Lee, Jee Eun Lee, Chongwoo Yu and Sandhya Apparaju.
`
`Table of Contents
`
` 1
`
`
`
`
` Executive Summary ..................................................................................................... 2
`1.1 Recommendation................................................................................................... 2
`1.2 Phase IV Commitments......................................................................................... 2
`1.3 Summary of Important Clinical Pharmacology and Biopharmaceutics Findings . 2
`2 Question-Based Review ............................................................................................... 3
`2.1 General Attributes.................................................................................................. 3
`2.2 General Clinical Pharmacology............................................................................. 5
`2.3
`Intrinsic Factors ................................................................................................... 11
`2.4 Extrinsic Factors.................................................................................................. 11
`2.5 General Biopharmaceutics................................................................................... 12
`2.6 Analytical............................................................................................................. 18
`3 Detailed Labeling Recommendations ........................................................................ 19
`4 Appendix .................................................................................................................... 25
`
`OCP Filing Memo ............................................................................................... 25
`
`
`
`1
`
`(b)
`(4)
`
`

`

`1 Executive Summary
`
`1.1 Recommendation
`
`NDA 22-501 is acceptable from a Clinical Pharmacology perspective,
`provided an agreement can be reached with the sponsor pertaining to labeling
`language.
`
`1.2 Phase IV Commitments
`
`None.
`
`
`
`1.3 Summary of Important Clinical Pharmacology and Biopharmaceutics
`Findings
`
`
`
`Warner Chilcott has submitted a new drug application (NDA) for
`.
` (or WC3016) is a low dose oral contraceptive
`consisting of a new dose and new regimen of the combination of
`norethindrone acetate (NA) and ethinyl estradiol (EE). The combination of
`10 µg of EE and 1 mg of NA (WC3016 1/10 tablets) is taken once daily for
`24 days, followed by two daily doses of 10 µg of EE (WC3016 EE10 tablets)
`and ferrous fumarate tablets (75 mg) for 2 days during a 28-day regimen.
`Three Loestrin NA/EE combination contraceptive products are
`currently approved in U.S. (see regulatory history further below in the QBR).
`These vary in the amounts of active ingredients (NA: 1 mg-1.5 mg; EE: 20 –
`30 µg) and in the total active treatment duration (21 days vs. 24 days).
` or WC3016 was formulated to investigate if the dose of
`estrogen could be further reduced while still retaining the efficacy of the
`higher dose products. The dose of EE was reduced to 10 µg and the 24-day
`treatment with active hormone previously shown to be safe and effective for
`Loestrin 24 Fe, was extended by adding 2 days of EE 10 mcg alone.
`Three Clinical Pharmacology Phase 1 studies and one Phase 3 safety
`and efficacy trial were conducted in support of this NDA. Results from the
`Clinical Pharmacology studies are summarized:
`
`Pharmacokinetics:
`
` tablets, the
`EE: Following once-daily administration of
`mean Cmax and AUCτ values for EE were 72 ± 22 pg/mL and 633 ± 235
`pg.h/mL, respectively on day 24. Accumulation based on Cmax and AUCτ of
`EE was 1.4- & 1.6-fold, respectively. Steady-state was achieved by day 13 on
`average.
`
`NE: The mean Cmax and AUCτ values for norethindrone (NE) on day 24
`were 13803 ± 4279 pg/mL and 84375 ± 31220 pg.h/mL, respectively.
`
`
`
`2
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Following once-daily administration of NA 1 mg as part of WC3016-1/10
`tablets, ~ 1.8-fold and 2.4-fold accumulation of NE was observed for Cmax and
`AUCτ respectively. NE concentrations more than doubled by Day 24 due to
`both accumulation and increased concentrations of sex-hormone binding
`globulin (SHBG) induced by EE. Steady-state was achieved for NE by day 13
`on average.
`
`Relative bioavailability:
`
`WC3016 1/10 tablets: Compared to a hydroalcoholic solution of NA/EE, the
`Cmax of EE and NE from the 1/10 tablets were lower by ~ 23 % and 42 %,
`respectively, while the AUC values were comparable. The 90 % C.I.
`surrounding the treatment mean ratios for AUCs were within 80-125 %.
`EE10 tablets: The Cmax and AUC of EE from the 10 µg EE tablet were
`bioequivalent to that of the solution formulation of EE. The 90 % C.I.
`surrounding the treatment mean ratios were within 80-125%.
`
`Food Effect:
`
`WC3016-1/10 tablets:
`When tablets were dosed under fed conditions [high calorie, high fat
`meal], the mean Cmax value for EE was reduced by ~ 23 %. The AUC values
`for EE remained relatively unchanged when dosed with food. The 90 % CI
`for AUC was within the 80-125 % range.
`When WC3016-1/10 tablets were dosed under fed conditions, the
`mean Cmax value for NE was unchanged, while the AUC increased ~ by 24 %
`relative to fasted conditions. The 90 % C.I. surrounding the treatment mean
`ratios of the AUC parameters fell outside the 80-125 % range.
`
`EE10 tablets:
`When EE 10µg tablet was administered under fed conditions, the Cmax
`was reduced by ~ 31 %, while the AUC parameters remained relatively
`unchanged compared to dosing under fasting conditions.
`
` was
`The Phase 3 clinical efficacy and safety trial for
`conducted without regard to meals. Therefore, it is acceptable to administer
` with or without meals.
`
`
`
`
`
`2 Question-Based Review
`
`2.1 General Attributes
`
`What pertinent regulatory background or history contributes to the current
`assessment of the clinical pharmacology and biopharmaceutics of this drug?
`
`3
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`• Warner Chilcott has submitted a new drug application for
` a
`low dose oral contraceptive consisting of a new dose and new regimen of the
`combination of NA and EE.
`• Three versions of Loestrin Fe that contain NA/EE have been previously approved
`(since 1973):
`o NDA 17-354 Loestrin Fe 1 mg/20 µg NA/EE tablets, USP and Ferrous
`Fumarate (75 mg) tablets
`o NDA 17-355 Loestrin Fe 1.5 mg /30 µg NA/EE tablets, USP and Ferrous
`Fumarate (75 mg) tablets.
`o NDA 21-871 Loestrin 24 Fe 1 mg /20 µg NA/EE tablets, USP and Ferrous
`Fumarate (75 mg) tablets
` or WC3016 was formulated to investigate if the dose of estrogen
`could be further reduced while still retaining the efficacy of the higher dose
`products. The dose of EE was reduced to 10 µg and the 24-day treatment with
`active hormone previously shown to be safe and effective for Loestrin 24 Fe, was
`extended by adding 2 days of EE 10 mcg alone.
`
`•
`
`2.1.1. What are the highlights of the chemistry and physical-chemical properties of the
`drug substance and the formulation of the drug product as they relate to clinical
`pharmacology and biopharmaceutics review?
`
`• The chemical structures of the two active components are shown:
`
`
`Figure 1: Chemical structure of Ethinyl Estradiol (EE)
`
`
`
`
`Figure 2: Chemical structure of Norethindrone Acetate (NA)
`
`• Molecular Weights: 340.46 (NA) and 296.40 (EE)
`• Molecular Formulae: C22H28O3 (NA) and C20H24O2 (EE)
`
`• Drug product information:
`
`4
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`o The combination tablet containing 1 mg NA and 10 mcg EE has the
`following inactive ingredients: mannitol, microcrystalline cellulose,
`FD&C Blue No. 1 Aluminum Lake, sodium starch glycolate, magnesium
`stearate, povidone, vitamin E and lactose monohydrate.
`o The 10 µg EE tablets contain the following inactive ingredients: mannitol,
`microcrystalline cellulose, sodium starch glycolate, magnesium stearate,
`povidone, vitamin E and lactose monohydrate.
`o Each ferrous fumarate 75 mg tablet contains mannitol, povidone,
`microcrystalline cellulose, sodium starch glycolate, magnesium stearate,
`sucralose and spearmint flavor. The ferrous fumarate tablets do not serve
`any therapeutic purpose.
`
`
`2.1.2. What are the proposed mechanism(s) of action and therapeutic indication(s)?
`
`
`•
`
` is indicated for the prevention of pregnancy in women
`
`
`
`• Combination oral contraceptives act by suppression of gonadotropins. Although
`the primary mechanism of this action is inhibition of ovulation, other alterations
`include changes in the cervical mucus (which increase the difficulty of sperm
`entry into the uterus) and the endometrium (which reduce the likelihood of
`implantation).
`
`
`
`2.1.3. What are the proposed dosage(s) and route(s) of administration?
`
`• The formulation is administered via the oral route. The dosage of
`is one tablet containing NA and EE daily for 24 consecutive days, followed by
`one tablet containing EE daily for 2 consecutive days, followed by one tablet
`containing ferrous fumarate daily for 2 consecutive days.
`
`2.2 General Clinical Pharmacology
`
`
`
`
`
`2.2.1 What are the design features of the clinical pharmacology and clinical studies
`used to support dosing or claims?
`
`Three Phase 1 Clinical Pharmacology studies and a Phase 3 safety and efficacy
`trial were conducted in support of this new formulation:
`
`• Study RR-00108/ Protocol PR-14206: A study to characterize the bioavailability
`of EE and Norethindrone (NE) following multiple-dose administration of
`WC3016 tablets in healthy female volunteers. This was a single center, single-
`treatment, multiple-dose, bioavailability characterization study in N = 18 healthy
`female subjects (ages 18-35 years). Data from 15 subjects is included as pre-dose
`concentrations of NE or EE were found prior to first dose in 3 subjects.
`
`5
`
`
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`• Study RR-09207/ Protocol PR-14006: A study to assess the bioavailability of EE
`and NE following oral administration of a WC3016 1/10 tablet (fasted) as
`compared to both a WC3016 tablet (fed) and an EE/NA solution (fasted) in
`healthy female volunteers. This was a single center, randomized, balanced,
`single-dose, 3-treatment. 3-period, 6-sequence crossover study in N =24 females.
`
`• Study RR09007/ Protocol PR-14106.0: A study to assess the bioavailability of EE
`following oral administration of a WC3016 EE10 tablet (fasted) as compared to
`both a WC3016 EE10 tablet (fed) and a EE solution (fasted) in healthy female
`volunteers. This was a single-center, randomized, balanced, single-dose, 3-
`treatment, 3-period, 6-sequence, crossover study in N = 24 healthy female
`subjects (18-35 years).
`
`• Study PR-05806 (Phase 3): An Open-Label Study of the Safety and Efficacy of a
`New Low Dose Oral Contraceptive Containing NA and EE. This was an open-
`label, uncontrolled, multicenter study that enrolled approximately 1,600
`heterosexually active women aged 18 to 45 years and at risk of becoming
`pregnant, who were assigned to take WC3016 daily for thirteen 28-day cycles of
`treatment [see clinical review by Dr. Ron Orleans for a discussion of the safety
`and efficacy outcomes].
`
`
`2.2.2 What is the basis for selecting the response endpoints (i.e., clinical or surrogate
`endpoints) or biomarkers (collectively called pharmacodynamics (PD)) and how are
`they measured in clinical pharmacology and clinical studies?
`
`• Pregnancy rate was the primary outcome measure in Phase 3 and is an appropriate
`endpoint for evaluating the efficacy of a contraceptive product.
`• The primary efficacy endpoint in the Phase 3 efficacy and safety study was the
`incidence of pregnancy, based on the Pearl Index (PI) in the group of women 35
`years of age or less based on all at-risk cycles where no other method of birth
`control was used.
`In addition, the PI for all subjects, regardless of age and based on all at-risk cycles
`where no other method of birth control was used, was also determined. The 95%
`confidence intervals for the Pearl Indices and life-table estimates of a subject
`becoming pregnant were also presented.
`
`•
`
`
`2.2.3 Are the active moieties in the plasma (or other biological fluid) appropriately
`identified and measured to assess pharmacokinetic parameters?
`
`• Yes. Plasma samples were analyzed for EE and NE by
`
` using a validated gas chromatographic method with mass spectrometric
`detection (GC/MS). The validation report and study assay reports were reviewed
`and found to demonstrate suitability of the assay for determination of EE and NE
`in human plasma.
`
`6
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2.2.4 Pharmacokinetics
`
`2.2.4.1 What are the single dose and multiple dose PK parameters?
`
`• Study RR-00108/ Protocol PR-14206 was a single center, single-treatment,
`multiple-dose, bioavailability characterization study that evaluated the single dose
`and multiple dose pharmacokinetics of NE and EE from the proposed formulation
`in healthy female volunteers (N = 18; ages 18-35 years); PK data from 3 subjects
`was excluded by sponsor per protocol as these individuals had unexplained pre-
`dose concentrations of the analytes that may suggest use of other oral
`contraceptive products.
`
`• Treatments:
`1 tablet containing 1 mg NE and 10 mcg EE per day on days 1-24
`1 tablet containing 10 mcg EE per day on days 25-26
`
`• PK sampling was done on days 1, 24 and 26 at pre-dose, and at 0.33, 0.67, 1,
`1.33, 1.67, 2, 2.5, 3, 4, 6, 9, 12, 16, 24 hours post-dose. Additional samples were
`obtained just prior to receiving doses 5, 9, 13, 17, and 21 for assessment of
`steady-state. Blood samples for determination of serum sex-hormone binding
`globulin (SHBG) concentrations were collected prior to dosing on study day 1 and
`24 hours after receiving doses 1, 4, 8, 12, 16, 20, 24 and 26.
`
`• Analytical methodology: Plasma EE and NE concentrations were determined at
` using a validated GC/MS method. The lower limits of
`quantitation were 2.5 pg/ml and 25 pg/ml for EE and NE, respectively. SHBG
`levels in serum samples were determined using a commercially available
`immunoassay kit (IRMAZEN co SHBG, Zen Tech sa, Belgium). All results were
`reported as nmol/L. Assay was valid over a range of 10-250 nmol/L. The
`accuracy and precision data for calibration standards and QCs was acceptable
`(within 15 %).
`
`• Pharmacokinetic methods: PK parameters were determined for EE and NE on
`days 1, 24 and 26 using non-compartmental methods.
`
`
`EE Pharmacokinetics:
`
`• Following once-daily administration of 10 µg EE tablets for 24 days (as part of
`WC3016-1/10 24-tablet regimen), accumulation ratios based on Cmax and AUCτ
`of EE were 1.4- and 1.6-fold, respectively on day 24, compared to single dose
`data on day 1. Steady-state for EE was achieved on average by day 13 based on
`visual assessment of mean data. Tukey’s multiple comparison testing conducted
`by the sponsor suggests that the trough levels were not significantly different after
`the second dose of the drug.
`
`7
`
`(b) (4)
`
`

`

`• Accumulation of EE was not observed on day 26 (after two days of dosing with
`EE10 alone) relative to day 1 (when it was administered as part of the
`combination NA/EE1/10 tablet). This was because the EE exposure on day 26
`was lower by ~37 % compared to day 24 (last day of combination 1/10 tablet).
`Sponsor notes that absence of a contribution from the metabolic conversion of NE
`to EE after day 24 might be the reason for lower EE systemic exposure on day 26.
`
`
`
`EE Day 1
`EE Day 24
`EE Day 26
`
`0
`
`10
`
`20
`
`30
`
`40
`
`Time (h)
`
`50
`
`60
`
`70
`
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Ethinyl Estradiol Concentrations
`
`(pg/ml)
`
`
`
`Tmax (h)]
`
`Cmax (pg/ml)
`
`AUCτ
`(pg.h/ml)
`Cmin (pg h/ml)
`
`Cavg (pg.h/ml)
`
`T1/2 (h)
`
`-
`
`-
`
`-
`
`-
`
`0.97
`
`
`Figure 3: Mean (SD) plasma concentration-time profiles of EE from WC3016 tablets in
`healthy female volunteers on days 1, 24 and 26.
`
`Table 1: Pharmacokinetic parameters of EE from WC3016 1/10 tablets
`EE
`Day 1
`Day 24
`Day 26
`(NA/EE 1/10 tablets)
`(NA/EE 1/10 tablets)
`(EE10 tablets)
`1.33
`1.33
`1.33
`[1 -4]
`[0.33 - 2.0]
`[1-12]
`51.72 (14.3)
`72.08 (21.65)
`49.67 (20.1)
`[27.8 %]
`[30 %]
`[40 %]
`404 (121)
`633 (235)
`395 (198)
`[30 %]
`[37 %]
`[50 %]
`9.78 (7.96)
`6.69 (5.76)
`[81.42 %]
`[86.1 %]
`26.38 (9.82)
`16.48 (8.27)
`[37.25 %]
`[50.2 %]
`18.4 (9)
`[48.9 %]
`
`Accumulation
`Ratio
`1.57
`-
`RAUC
`Values reported are Mean (SD) [% CV]; for Tmax, mean [range] are reported. N =15
`
`
`
`
`
`
`
`
`Norethindrone pharmacokinetics:
`
`• Following once-daily administration of NE 1 mg as part of WC3016-1/10 tablets,
`~ 1.8-fold and 2.4-fold accumulation of NE was observed on day 24 for Cmax and
`AUCτ respectively, relative to single dose data on day 1. Based on visual
`
`8
`
`

`

`assessment of trough levels steady-state was achieved for NE by day 13 on
`average. Tukey’s multiple comparison testing was conducted by sponsor for
`steady-state assessment and data in general shows that the trough levels were not
`significantly different among doses after day 5. Serum SHBG concentrations
`doubled by day 24 [Fig 5]. Norethindrone concentrations more than doubled by
`day 24 due to both accumulation and increased SHBG concentration.
`
`18000
`16000
`14000
`12000
`10000
`8000
`6000
`4000
`2000
`0
`
`NE Day 1
`NE Day 24
`
`
`
`Norethindrone Concentrations
`
`(pg/ml)
`
`0
`
`5
`
`10
`
`15
`Time (h)
`
`20
`
`25
`
`30
`
`Figure 4: Mean (SD) plasma concentration-time profiles of NE from WC 3016
`tablets on days 1 and 24.
`
`Table 2: Plasma NE pharmacokinetics in healthy female subjects on days 1 & 24.
`
`
`
`9
`
`NE
`
`Tmax (h)
`
`
`Cmax (pg/ml)
`
`
`AUCτ (pg.h/ml)
`
`
`T1/2 (h)
`
`
`Day 1
`
`1.67
`[1.33-6.0]
`
`7683 (1959)
`[25.5 %]
`
`37100 (15667)
`[42 %]
`
`7.89 (2.31)
`[29 %]
`
`
`Day 24
`
`1. 33
`[1.0-2.5]
`
`13803 (4279)
`[31 %]
`
`84375 (31220)
`[37 %]
`
`8.86 (2.79)
`[31.5 %]
`
`
`2.4
`
`
`Accumulation
`(RAUC)
`-
`
`
`Values reported are mean (SD) [% CV]; Median [range] are
`reported for Tmax; N =15
`
`
`
`
`
`
`
`
`
`
`
`

`

`15
`Day
`
`20
`
`25
`
`30
`
`0
`
`5
`
`10
`
`180
`
`160
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`SHBG concentrations (nmol/L)
`
`
`
`Figure 5: Average SHBG concentrations (pre-dose) during once-daily administration of
`WC3016 1/10 tablets in healthy female volunteers (N = 15)
`
`2.2.4.2 What are the characteristics of drug absorption?
`
`
`• NA and EE are rapidly absorbed from
` tablets. Maximum
`plasma concentrations of NE and EE occur approximately 1 to 2 hours post-dose.
`Absolute bioavailability is reported to be approximately 64% for NE and 55% for
`EE.
`• When dosed as a WC3016 1/10 tablet, compared to a solution of the drugs the
`Cmax of EE and NE were lower but the AUC values were comparable. The EE
`alone 10 mcg tablets were bioequivalent to the EE solution.
`• For the WC3016 1/10 tablet, concomitant food intake reduced the Cmax of EE by
`23 %, but the AUC was unchanged. Food did not affect the Cmax of NE but
`increased AUC by ~ 24 %. When EE 10 µg alone tablet was administered under
`fed conditions, the Cmax was reduced by ~ 31 % relative to dosing under fasted
`conditions, but the AUC was relatively unaffected.
`• Phase 3 clinical trial for
` was done without regard to food. Hence
`it is acceptable to dose
` with or without food.
`
`2.2.4.3 What are the characteristics of drug distribution?
`
`• 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 to albumin. Although EE does not bind to SHBG, it
`induces SHBG synthesis. SHBG concentrations doubled following 24 days of
`dosing with
` combination tablets.
`
`
`2.2.4.4 What are the characteristics of drug metabolism?
`
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`• 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.
`• 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
`ethinyl estradiol, 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.
`
`2.2.4.5 What are the characteristics of drug excretion?
`
`(cid:131) 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 1 mg NA/10 µg
`EE tablets are approximately 9 hours and 18 hours, respectively.
`
`2.3 Intrinsic Factors
`
`Renal Impairment:
`• The effect of renal disease on the disposition of NE and EE after
`administration has not been evaluated.
`In premenopausal women with chronic renal failure undergoing peritoneal
`dialysis who received multiple doses of an oral contraceptive containing EE and
`NE, plasma EE concentrations were higher and NE concentrations were
`unchanged compared to concentrations in premenopausal women with normal
`renal function (information from the labeling).
`Hepatic Impairment:
`• The effect of hepatic disease on the disposition of NE and EE after
` administration has not been evaluated. However, EE and NE may be poorly
`metabolized in patients with impaired liver function.
`
`
`
`
`
`2.4
`
`Extrinsic Factors
`
` Drug-drug interactions
`
`• No specific drug-drug interaction studies were conducted for
`
`Changes in contraceptive effectiveness associated with co-administration of other
`products:
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`• Drugs or herbal products that induce such enzymes may decrease the plasma
`concentrations of contraceptive hormones, and may decrease the effectiveness of
`hormonal contraceptives or increase breakthrough bleeding. Some drugs or
`herbal products that may decrease the effectiveness of hormonal contraceptives
`include: barbiturates, bosentan, carbamazepine, felbamate, griseofulvin,
`oxcarbazepine, phenytoin, rifampin, St. John’s wort, topiramate.
`
` •
`
` HIV protease inhibitors: Significant changes (increase or decrease) in the plasma
`levels of the estrogen and progestin have been noted in some cases of co-
`administration of HIV protease inhibitors.
`
` •
`
` Antibiotics: There have been reports of pregnancy while taking hormonal
`contraceptives and antibiotics, but clinical pharmacokinetic studies have not
`shown consistent effects of antibiotics on plasma concentrations of synthetic
`steroids.
`
`
`Increase in plasma levels of estradiol associated with co-administered drugs:
`
` •
`
` Co-administration of atorvastatin and certain combination oral contraceptives
`containing ethinyl estradiol increase AUC values for ethinyl estradiol by
`approximately 20%. Ascorbic acid and acetaminophen may increase plasma
`ethinyl estradiol levels, possibly by inhibition of conjugation. CYP3A4 inhibitors
`such as itraconazole or ketoconazole may increase plasma hormone levels.
`
`
`Changes in plasma levels of co-administered drugs:
`
` •
`
` Combination OCs have been shown to significantly decrease plasma
`concentrations of lamotrigine likely due to induction of lamotrigine
`glucuronidation. This may reduce seizure control; therefore, dosage adjustments
`of lamotrigine may be necessary. Decreased plasma concentrations of
`acetaminophen and increased clearance of temazepam, salicylic acid, morphine
`and clofibric acid, due to induction of conjugation have been noted when these
`drugs were administered with combination oral contraceptives.
`• Combination hormonal contraceptives containing some synthetic estrogens (e.g.,
`ethinyl estradiol) may inhibit the metabolism of other compounds. Increased
`plasma concentrations of cyclosporine, prednisolone, and theophylline have been
`reported with concomitant administration of combination oral contraceptives.
`
`
`2.5 General Biopharmaceutics
`
`2.5.1 What is the 1) relative bioavailability of the proposed WC3016 1/10 tablets (vs.
`solution) and 2) effect of food on the proposed WC3016 1/10 formulation?
`
`• The relative bioavailability and food-effect of the NA/EE 1/10 tablets compared
`to a NA/EE 1/10 solution was evaluated in study # RR09207. This was a single
`
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`center, randomized, balanced, single-dose, 3-treatment, 3-period, 6-sequence
`crossover study in ~ N= 24 healthy female, non-smoking subjects ages 18-35
`years inclusive;
`
`(cid:131) Subjects received 3 treatments in a cross over manner in one of the three periods
`(6 possible sequences ABC, ACB, BCA, BAC, CAB, CBA). Each drug treatment
`was separated by a washout of 28 days. In the fed group, subjects received a high-
`fat, high-calorie breakfast which was consumed over 25-30 minutes and drug was
`administered within 5 minutes of completion.
`
`
`
`
`
`o Treatment A: One WC3016-1/10 Tablet containing 1 mg NA and 10 µg
`EE /fasted; 240 ml water
`o Treatment B: One WC3016-1/10 Tablet containing 1 mg NA and 10 µg
`EE /fed; 240 ml water
`o Treatment C: 120 ml solution containing 1 mg NA and 10 µg EE /fasted;
`120 ml water
`
`
`Ethinyl Estradiol:
`
`
`
`
`Study RR 09207 Plasma EE concentrations
`
`Trt A [tablet/fasted]
`Trt B [tablet/fed]
`Trt C [solution/fasted]
`
`0
`
`10
`
`20
`
`40
`30
`EE concentrations (pg/ml)
`
`50
`
`60
`
`70
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Time (h)
`
`
`Figure 6: Plasma concentration-time profiles of EE after single doses of WC3016 tablets
`or solution [A: 1/10 tablet/fasted; B: 1/10 tablet/fed; C: 1/10 solution]
`
`Table 3: Single dose plasma pharmacokinetics of EE
`
`
`EE PK
`Study RR09207
`Cmax (pg/ml)
`Tmax (h)
`AUCtldc
`(pg.h/ml)
`AUCinf (pg.h/ml)
`
`
`
`Trt A
`[Tablet/fasted]
`n =19-22*
`53.1 ± 15.5
`1.33 [1.0-4.0]
`
`Trt B
`[Tablet/fed]
`N=18-22*
`41.3 ± 12.1
`2.5 [0.67-6.0]
`
`Trt C
`[Solution/fasted]
`N = 21-22*
`67.7 ± 14.9
`1.33 [0.67-1.67]
`
`476.1 ± 167.5
`551 ± 216
`
`491.4 ± 200.1
`586.5 ± 228.4
`
`488.2 ± 161.2
`558.6 ± 191.7
`
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`T1/2 (h)
`16.2 ± 8.24
`16.48 ± 13.59
`Values indicate Mean ± SD; Tmax: Median [Range]
`* Terminal elimination rate constant couldn't be estimated from all individuals and
`hence T1/2 and AUCinf couldn’t be computed from all 22 subjects.
`
`13.46 ± 7.27
`
`
`Relative bioavailability of EE from WC3016 1/10 tablets:
`
`
`• Compared to a solution of EE, the rate of absorption from the tablet was slower as
`evidenced by a smaller Cmax value and a wider Tmax range. The extent of EE
`absorption was not significantly different between the two formulations.
`• Statistical comparison using the average bioequivalence approach for the
`geometric means of test (Trt A) vs. reference (Trt C) confirms that the AUC is
`comparable as the 90 % confidence interval for the geometric mean ratios of
`test/reference are within the 80-125 % range.
`
`
`Table 4: Statistical results for EE - Relative bioavailability of tablets vs. solution
`
`
`EE
`PK Parameter
`Cmax
`
`AUC0-tldc
`
`AUCinf
`
`Ratio
`(Tablet/Solution)
`77.63
`
`96.14
`
`97.37
`
`90 % CI
`
`73.11 – 82.