Oral emergency contraception: an efficacy and regulatory update Rebecca Stone, PharmD, BCPS, BCACP Marlowe Djuric Kachlic, PharmD University of Illinois at Chicago College of Pharmacy UI Hospital and Health Sciences System (UIHHS)

Disclosures/Conflict of Interest

• The speakers declare no conflicts of interest, real or apparent, and no financial interests in any company, product or service mentioned in this program, including grants, employment, gifts, stock holdings and honoraria.

Objectives Pharmacists At the conclusion of this program, the pharmacist will be able to:

• Explain the mechanism of action for available oral emergency contraception (EC) products as supported by current research.

• Describe the recent changes in levonorgestrel (LNG) EC labeling in the international setting and implications in the US.

• Interpret the evidence available regarding oral EC efficacy, including LNG and ulipristal acetate (UPA).

• Explain the legal regulations surrounding patient purchase of oral LNG EC and UPA EC, and recommend appropriate EC for a patient.

Objectives Pharmacy Technicians At the conclusion of this program, the pharmacy technician will be able to:

• Describe the appropriate time period for patients to utilize oral EC methods.

• Explain the legal regulations surrounding patient purchase of oral LNG EC and UPA EC.

• Describe where different types of EC products may be stocked in the pharmacy.

BACKGROUND

Unintended pregnancy in the United States 6.7 million pregnancies

Birth 22%

Intended Pregnancy 51%

Unintended Pregnancy 49%

Abortion 20%

Miscarriage 7%

Finer et al. Contraception. 2011.

Physiology definitions • Ovulation •

Lutenizing hormone (LH) increases and triggers the release of an oocyte (egg) from the ovary

• Pregnancy •

Zygote (fertilized egg) successfully implants into the endometrium (uterine lining)

Conception • Sperm must fertilize oocyte within 24 hours of ovulation • •

Oocyte survival is 24 hrs Sperm can survive in the female reproductive tract for 5 days

• Fertile window •

5 days before ovulation to 1 day after

Gemzell-Danielsson K. Contraception. 2013; Trussell J. Contraception. 1998; Wilcox AJ. NEJM. 1995; Wilcox AJ. Hum Reprod 2004

Probability of conception on specific days near the day of ovulation

Ovulation Wilcox AJ. N Engl J Med. 1995.

Conception • Assessing time of ovulation is difficult •

Discrepancy

• •

•

Patient reported stage of menstrual cycle Dating based on endocrine data

Unprotected intercourse outside of the supposed fertile period may still result in pregnancy

Gemzell-Danielsson et al. Contraception. 2013; Novikova et al. Contraception. 2007; Wilcox et al. BMJ. 2000.

Probability of clinical pregnancy with one act of intercourse relative to day of the menstrual cycle 1st day of menses

Ovulation

EC should be administered regardless of cycle day to prevent an unwanted pregnancy

Wilcox AJ. Contraception. 2001.

Allen et al. Contraception. 2001

Conception probability Days prior to Probability of Ovulation Conception 5 4 3 2 1 0

3.6% 13.6% 15.5% 27.7% 29.8% 12.3%

• Overall pregnancy rate expected in absence of EC is 5.6%

• FDA and European Medicines Agency (EMA) established a pregnancy rate of < 4% as the EC efficacy benchmark

Glasier A. Contraception. 2011; Trussell J. Contraception. 1998; Wilcox AJ. NEJM. 1995.

Percentage of sexually experienced women aged 1544 who have ever used emergency contraception Percentage ever used

Frequency of use

12%

100%

10%

80%

17% 24%

8%

60%

6%

Twice

40%

4%

Three or more

59%

2%

20%

0%

0% 1995

2002

Daniels et al. NCHS Data Brief. 2013

2006-2010

Once 2006-2010

EMERGENCY CONTRACEPTIVE AGENTS

EC products in the US Copper-T IUD

UPA EC

LNG EC

Copper-T IUD • Paragard® • •

Placed within 5 days after intercourse Efficacy

• • •

•

Most effective method Effectiveness does not decline with delay Failure rate < 1%

Prescription only

Trussell, 2011. http://ec.princeton.edu/questions/ec-review.pdf.

Copper-T IUD: MOA • Enhances the inflammatory response, reaching levels that are toxic for sperm

•

Diminishes sperm penetration, impairs motility

• Emergency contraception is off label use • • •

Placed by trained clinician More barriers to access Provides long term contraception

Gemzell-Danielsson et al. Contraception. 2013; Ortiz et al. Obstet Gynecol Surv. 1996; Roblero et al. Reprod Fertil Dev. 1996.

UPA EC • Ella® •

Dose

•

•

Administration

•

•

Take within 5 days after intercourse

Efficacy

• •

•

30 mg x 1 dose

Approved for a longer window than LNG EC More effective than LNG EC

Prescription only

UPA EC: MOA • 2nd generation selective progesterone receptor modulator • No effect on sperm function • Direct inhibitory effect on follicular rupture •

Decreased efficacy, but may still work even when luteinizing hormone (LH) has started to rise

• Likely does not effect embryo implantation

Gemzell-Danielsson et al. Contraception. 2013; Brache et al. Hum Reprod. 2010.

LNG EC • Levonorgestrel •

Dose

• •

•

1.5 mg x 1 dose

Administration

• •

•

0.75 mg x 2 doses

Take within 72 hours after intercourse Off label – may take up to 5 days after intercourse

OTC, BTC, & prescription

LNG EC: MOA • Progestin • No effect on sperm function • Affects follicular development after dominant follicle selection •

ONLY before rise in LH

• No effect on embryo implantation

Gemzell-Danielsson K. Contraception. 2013.

Percent of embryo attached

In vitro model for human embryo implantation 70%

No significant difference

60% 50% 40% 30% 20% 10%

6/14

10/17

0/15

Control

Levonorgestrel

Mifepristone

0% Treatment Groups Gemzell-Danielsson K. Contraception. 2013; Lalitkumar PGL. Hum Reprod. 2007.

EC adverse events 20.0% 18.0% 16.0% 14.0% 12.0% 10.0% 8.0% 6.0% 4.0% 2.0% 0.0%

UPA (n=1104) LNG (n=1117)

Glasier et al: LNG vs UPA EC Glasier et al. Lancet. 2010.

LNG & UPA EC EFFICACY

Clinical trial meta-analysis

Limited UPA data UPA Published Studies LNG vs UPA RCTs

Observational

Crenin et al, 2006 UPA 7/773 pregnancies 0.91%

Glasier et al, 2010 UPA 15/941 pregnancies 1.59%

LNG 13/773 pregnancies 1.7%

LNG 25/958 pregnancies 2.6%

Fine et al, 2010 UPA 26/1241 pregnancies 2.10%

LNG comparators n = 1731

Abitbol JL. ASEC Webinar. May 2014; Glasier A. Lancet. 2010; Creinin MD. Obstet Gynecol. 2006.

Clinical trial design Crenin et al, 2006

Glasier et al, 2010

N = 1546

N = 1899

UPA = 773, LNG = 773

UPA = 941, LNG = 958

UPA Phase II trial

UPA Phase III trial

Received EC within 72 hr

Received EC within 120 hr

0.75 mg x 2 doses

1.5 mg x 1 dose

Weight measured

Weight self reported

Glasier A. Lancet. 2010. Creinin MD. Obstet Gynecol. 2006.

EFFICACY AND BODY WEIGHT

Question #1

LNG EC may be less effective in women weighing more than 165 lbs.

a. True b. False

Pregnancy risk according to BMI 7.0%

Percent pregnant

6.0%

UPA

5.8%

LNG

5.0% 4.0% 3.0%

2.5%

2.0%

1.3%

1.1%

2.6%

1.1%

1.0% 0.0% 30

Pregnancy rate following LNG EC according to weight categories

Weight (kg)

< 55

55-65

65-75

75-85

≥85

N total

349

608

426

155

193

N pregnancies

3

8

6

10

11

Pregnancy rate

0.9%

1.3%

1.4%

6.4%

5.7%

95% Confidence interval Kapp et al. Contraception. 2015

0.2-2.5 0.6-2.6 0.5-3.0 3.1-11.5

2.910.0

LNG EC pregnancy probability by weight

Kapp et al. Contraception. 2015

Clinical trial limitations • • •

Exploratory analyses

•

Neither trial designed to evaluate the effect of weight on the effectiveness of EC

Weight was self reported in Glasier et al. 2010

•

~55% of patients

Limited number of pregnancies (n=38)

• •

BMI of 30 or greater (n=242) Pregnancies with BMI of 35 or greater “extremely small”

Glasier A. Contraception. 2011.

LNG EC European labeling • NorLevo label was changed in Europe & Canada in late 2013 •

“In clinical trials, contraceptive efficacy was reduced in women weighing 75 kg or more, and LNG was not effective in women who weighed more than 80 kg”

• NorLevo® distributor • • •

HRA Pharma Distributes product to over 50 countries

Sole manufacturer of UPA

Norlevo Package Insert. 2013.

Previous clinical trial data • Effect not reported in previous studies • •

Mean body weight much lower

Different demographics

•

Predominantly Asian and African population

Von Hertzen H. Lancet. 1998; Von Hertzen H. Lancet. 2002; Dada O. Contraception. 2010.

Previous published trial data Clinical Trial

Trial design

LNG EC demographic data

LNG EC pregnancy rate

n = 976 Mean BMI 22.0

11/976 1.1%

Von Hertzen et al Lancet 1998

• LNG vs. Yuzpe method • EC taken ≤ 72 hrs • 21 study sites

Von Hertzen et al Lancet 2002

• Mifepristone vs. LNG 1 dose vs. LNG 2 dose • EC taken ≤ 120 hrs • 15 study sites

n = 2712 Mean weight 56.2 kg

44/2712 1.62%

Dada et al Contraception 2010

• LNG 1 dose vs. LNG 2 dose • EC taken ≤ 120 hrs • 7 sites (all Nigeria)

n = 2823 Mean BMI 24.2

17/2823 0.61%

LNG comparators n = 6511

Data implementation •

European Medicines Agency 7/2014

• • •

•

“LNG EC can continue to be used in women of all weights as the benefits are considered to outweigh the risks” EMA reviewed three WHO trials and stated they did not find reduced efficacy with increasing weight or BMI Statement was removed from the label

FDA continues to review available data

Cause of weight related decrease in LNG efficacy? • Unknown if efficacy is decreased by metabolic or pharmacokinetic changes • No data evaluating higher doses of LNG • Decreased efficacy with other hormonals • •

Contraceptive patch (90 kg warning) Combined oral contraceptives

Question #1

LNG EC may be less effective in women weighing more than 165 lbs.

a. True b. False

Question #1

LNG EC may be less effective in women weighing more than 165 lbs.

a. True b. False

REGIMEN TIMING AND EFFICACY

Question #2

LNG EC can be effective if taken up to 5 days after unprotected intercourse.

a. True b. False

Question #3

LNG EC is more effective than UPA EC when taken on day 5 following intercourse.

a. True b. False

Timing and Efficacy • Always give EC as soon as possible • When stratified by time, UPA was found to have lower failure rates than LNG

• • •

odds ratio for pregnancy 65% lower in the first 24 hours odds ratio for pregnancy 42% lower up to 72 hours

odds ratio for pregnancy45% lower up to 120 hours

Glasier et al. Lancet. 2010

Timing and efficacy • Related to MOA • When ovulation is imminent, UPA is more effective than LNG in delaying it if administered within 5 days

• •

If the follicle reaches 15–17 mm, LNG is not able to prevent follicular rupture better than placebo If the leading follicle reaches 18–20 mm, UPA prevents follicular rupture in 59% of cycles compared with 0% in placebo cycles

Croxatto et al. Contraception, 2004; Brache et al. Hum Reprod 2010

Repeated acts of intercourse following EC use • Repeated acts of intercourse following EC use increase the likelihood of pregnancy with both LNG and UPA EC

• Women should use back up with progestin containing contraceptives following use of Ella

•

Mechanism may render them ineffective

Question #2

LNG EC can be effective if taken up to 5 days after unprotected intercourse.

a. True b. False

Question #2

LNG EC can be effective if taken up to 5 days after unprotected intercourse.

a. True b. False

Question #3

LNG EC is more effective than UPA EC when taken on day 5 following intercourse.

a. True b. False

Question #3

LNG EC is more effective than UPA EC when taken on day 5 following intercourse.

a. True b. False

WHAT IS THE NEXT STEP?

Efficacy summary • Efficacy declines over time for all oral EC • Women are not able to reliably assess how close they are to ovulation • “Is LNG today more effective than UPA tomorrow?” • Currently there is no data to gauge the efficacy impact of delaying EC in order to obtain UPA

Planned Parenthood

http://www.plannedparenthood.org/health-center. Accessed 6/2/2014.

My perspective • Risk vs benefit of EC types should be discussed at well woman visits •

Ella® script should be provided in advance

•

However, do not significantly delay EC administration

• Copper IUD is the most effective type of EC • When using oral EC, ella® should be first choice • LNG EC is better than no EC! •

In absence of conclusive studies, provide information about potential relationship between weight and efficacy

LEGAL AND REGULATORY INFORMATION

History of EC dispensing in Illinois • In 2005, former governor Blagojevich signed "emergency rule" which required pharmacists to dispense EC with a valid prescription without delay

•

Pharmacists could be fined or lose their license if they refused to fill

• Challenged by 2 pharmacists citing the Conscience Act and the Freedom of Religion Act

“Emergency Contraception: Law and Ethics” http://www.uspharmacist.com/content/d/pharmacy_law/c/37747/ “Beyond the Issue of Pharmacist Refusals: Pharmacies that Won’t Sell Emergency Contraception” http://www.guttmacher.org/pubs/tgr/08/3/gr080310.html

History of EC dispensing in Illinois • In 2009 the circuit court granted an injunction to the pharmacists prohibiting the state from enforcing the law

• The rule was amended in April 2010 stating pharmacies had a “duty to deliver lawfully prescribed drugs to patients and distribute nonprescription drugs”

•

EC not mentioned, neither was conscience- or religious-based objections

Pharmacy organization stance • APhA •

Added a conscience clause to the Code of Ethics in 1998

• ACCP •

Position statement in 2005

• Both recognize that a pharmacist has the right to conscientiously refuse to dispense certain medications, but encourages that policies be developed to ensure medication delivery to the patient in a timely manner “Prerogative of a Pharmacist to Decline to Provide Professional Services Based on Conscience” http://www.accp.com/docs/positions/positionStatements/pos31_200508.pdf

“State Policies in Brief: Emergency Contraception” http://www.guttmacher.org/statecenter/spibs/spib_EC.pdf

Laws surrounding EC dispensing

• Pharmacies must fill valid prescriptions for EC •

Unless they refuse

• Illinois law allows for refusal to dispense EC by pharmacists and pharmacies •

Broadly worded--refusal may apply to either but does not specifically include them

60

A brief legal history of LNG • May 1999 – Plan B approved as Rx drug by FDA • August 2006 – Plan B approved as OTC for consumers 18 and older (Rx for 17 and younger)

• April 2009 – Plan B approved for sale OTC to women and men 17 and older • December 2011 – FDA was to approve Plan B with no age restriction— overruled by HHS Secretary Kathleen Sebelius

“History of Plan B OTC” http://ec.princeton.edu/pills/planbhistory.html “The Fight for Emergency Contraception: Every Second Counts” http://reproductiverights.org/en/print/1133

A brief legal history of LNG • 2012 – Teva files amended application to the FDA to make Plan B One Step available OTC to consumers 15 and over and not BTC

• April 2013 – Amendment approved by FDA • June 2013 – Plan B One Step approved by FDA for unrestricted sale OTC • February 2014 – FDA approves generic one-pill EC products for unrestricted sale OTC

FDA Orange Book http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=021998&TABLE1=OB_OTC http://www.hpm.com/pdf/blog/PLAN%20B%20-%20FDA%20Exclusivity%20&%20Carve-Out%20Determination.pdf

Question #4

Plan B One Step ® can be purchased by a 15 year old male, without proof of age, as an over-the-counter item.

a. True b. False

Definitions • Behind the Counter • • •

Purchaser must be 17 years and older with valid ID Can be male or female Purchased from the pharmacy (not available on the shelves)

• Over the Counter •

Anyone of any age can purchase

•

•

No ID required for purchase

Available in the “Family Planning” aisle instead of behind the pharmacy counter

Prescription status

• The 2-pill regimens (LNG 0.75mg tabs) are prescription only •

Mostly manufacturer discontinued at this point

• Patients can talk to the pharmacist about running the OTC EC as a prescription to get coverage through insurance (i.e. IHFS)

Which products are truly OTC? Product name (levonorgestrel 1.5mg)

Label

Price

Plan B One Step

Available OTC unrestricted

~$50

Take Action

Available OTC unrestricted

~$40

MyWay

Available OTC for 17 and older*

~$30

Next Choice One Dose

Available OTC for 17 and older*

~$40

Fallback Solo

Available OTC for 17 and older*

~$50

Opcicon One-Step

Available OTC for 17 and older*

~$30

AfterPill

www.afterpill.com

$20 + $5 shipping

Drug Facts and Comparisons July 2015 www.drugstore.com www.drugs.com McKesson Connect connect.mckesson.com

*Labeled as such; ID not required to purchase

Why is this important?

ACCESS!

Access issues •

Study done in 2013 illustrated the barriers and false information given by pharmacists to females seeking EC

•

•

Survey done in 2014 demonstrated that young men have a 1 in 5 chance of not being able to obtain EC

•

•

943 pharmacies were called, 57% gave correct information about EC access

158 pharmacies, 22 required a female at the time of purchase

Study done in 2005 looked at EC use in adolescents when it was readily available

•

No difference in use of routine contraception; no increase in risky sexual behavior

Why are there barriers to access?

• Ethics • Education • Safety • Cost

ella®

• Requires prescription for all ages • Can get through some websites (don't have to see a physician)

• ~$60 https://pharma.afaxys.com/afaxys/afcor_web_hcp_ella.html http://www.ella-kwikmed.com/

70

ella® availability • Distributed by Afaxys •

Previous distributor dropped ella® in early 2014

• OTC status for Ella®? •

Recommended for OTC availability by European Medicines Agency in 2014

• Widely available to order through McKesson, Cardinal, Smith, ANDA Wood, S. ASEC Webinar. May 2014. RHTP FAQ Handout, 2013. http://www.rhtp.org/contraception/emergency/documents/FAQ.ECEfficacyandBodyWeight.December2013.pdf Accessed 6/2/14 Afaxys Full Line Product Catalog

Paragard®

• Requires prescription for all ages • Must be inserted by a specially trained provider • ~$800 http://www.paragard.com/What-it-costs.aspx

72

EC availability summary • PlanB One-Step and Take Action available OTC for all ages • Some one dose branded generics still BTC/Rx •

No ID verification required

• Two dose generics are BTC/Rx •

Manufacturer discontinue

• ella® and Paragard® available only by prescription

Question #4

Plan B One Step ® can be purchased by a 15 year old male, without proof of age, as an over-the-counter item.

a. True b. False

Question #4

Plan B One Step ® can be purchased by a 15 year old male, without proof of age, as an over-the-counter item.

a. True b. False

Questions?

References • • • • • • • • • • • •

Allen J. Wilcox , David B. Dunson , Clarice R. Weinberg , James Trussell , Donna Day Baird. Likelihood of conception with a single act of intercourse: providing benchmark rates for assessment of post-coital contraceptives. Contraception, Volume 63, Issue 4, 2001, 211 – 215 Bell DL, Camacho EJ, Velasquez AB. Male access to emergency contraception in pharmacies: a mystery. Contraception 2014; 90:413-415. Brache V, Cochon L, Jesam C, et al. Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays follicular rupture. Hum Reprod 2010;25:2256– 63. Creinin MD, Schlaff W, Archer DF, et al. Progesterone receptor modulator for emergency contraception: a randomized controlled trial. Obstet Gynecol. 2006 Nov;108(5):1089-97. Croxatto HB, Brache V, Pavez M, et al. Pituitary-ovarian function following the standard levonorgestrel emergency contraceptive dose or a single 0.75-mg dose given on the days preceding ovulation. Contraception. 2004 Dec;70(6):442-50 Dada OA, Godfrey EM, Piaggio G, et al. A randomized, double-blind, noninferiority study to compare two regimens of levonorgestrel for emergency contraception in Nigeria. Contraception. 2010 Oct;82(4):373-8. Daniels K, Jones J and Abma J, Use of emergency contraception among women aged 15–44: United States, 2006–2010, NCHS Data Brief, 2013, No. 112, , accessed Jun 2, 2013. FDA approves Plan B One-Step emergency contraceptive for use without a prescription for all women of child-bearing potential. June 20, 2013. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm358082.htm Accessed 6/5/2014. Finer LB, Zolna MR. Unintended pregnancy in the United States: Incidence and disparities, 2006. Contraception. Nov 2011; 84(5): 478–485.

Gazdag M, Kardos L, Frey B, Kapp N, Philip M. (2014 June 4) Women’s BMI as a factor in EC failure. An open discussion on the data available to date [Webinar]. Hosted by the International and Eurpoean consortium for Emergency Contraception. Gemzell-Danielsson K, Berger C, Lalitkumar P.G.L. Emergency contraception — mechanisms of action. Contraception 2013;87:300–308. Glasier A, Cameron ST, Fine PM, et al. Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis. Lancet 2010; 375: 555–62

References • • • • • • • • • • • •

Glasier A, Cameron ST, Blithe D, et al. Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel. Contraception. 2011 Oct;84(4):363-7 Gould JE, Overstreet JW, Hanson FW. Assessment of human sperm function after recovery from the female reproductive tract. Biol Reprod 1984;31:888–94. Guttmacher Institute. State Policies In Brief. Available at: https://www.guttmacher.org/statecenter/spibs/spib_EC.pdf. Accessed June 4, 2014.

Kapp N, Abitbol JL, Mathé H, et al. Effect of body weight and BMI on the efficacy of levonorgestrel emergency contraception. Contraception. 2015 Feb;91(2):97-104. Lalitkumar PGL, Lalitkumar S, Meng CX, et al. Mifepristone but not levonorgestrel inhibits human blastocyst attachment to an in vitro endometrial three-dimensional cell culture model. Hum Reprod 2007;22:3031–7. NorLevo 1.5 mg tablet [Package Leaflet: Information for the user]. Paris, France: HRA Pharma; 2013 http://www.imb.ie/images/uploaded/swedocuments/2126041.PA1166_002_001.a60606c0-00f0-4866-bc3491bdfd679b1e.000001PACKAGE%20LEAFLET%201.5.131128.pdf Accessed 12/18/13. Novikova N, Weisberg E, Stanczyk FZ, Croxatto HB, Fraser IS. Effectiveness of levonorgestrel emergency contraception given before or after ovulation–a pilot study. Contraception 2007;75:112–8. Ortiz ME, Croxatto HB, Bardin CW. Mechanisms of action of intrauterine devices. Obstet Gynecol Surv 1996;51:S42–51. Plan B One-Step [Highlights of prescribing information]. Pomona, New York: Gedeon Richter, Ltd; 2009. http://www.planbonestep.com/pdf/PlanBOneStepFullProductInformation.pdf Accessed 6/5/2014. Planned Parenthood. “What’s the Best Emergency Contraception for You?”. 2013. http://www.plannedparenthood.org/health-center. Accessed 6/2/2014. Reproductive Health Technologies Project. “Where should EC Be.” Aug 2013. www.rhtp.org/contraception/emergency/documents/WhereShouldECBe.August12013.pdf. Accessed 6/5/2014. Reproductive Health Technologies Project. “Women’s Health Advocates Celebrate FDA Decision to Remove Restrictions on Generic Emergency Contraception. Generic Emergency Contraceptive Pills Move One Step Closer to Full Over-the-Counter Status. Feb 2013. http://www.rhtp.org/documents/RHTPPressReleaseFDADecisiontoRemoveRestrictionsonGenericEC.pdf Accessed 6/5/2014.

• • • • • • • • • •

• • •

References

Reproductive Health Technologies Project. “Frequently Asked Questions: The Impact of Weight on Efficacy of Emergency Contraception.” Dec 2013. http://www.rhtp.org/contraception/emergency/documents/FAQ.ECEfficacyandBodyWeight.December2013.pdf Accessed 6/2/2014. Roblero L, Guadarrama A, Lopez T, Zegers-Hochschild F. Effect of copper ion on the motility, viability, acrosome reaction and fertilizing capacity of human spermatozoa in vitro. Reprod Fertil Dev 1996;8:871–4. Shea, K. (2014 May14) EC in a Health Center Setting: the EC4U Project [Webinar]. In ASEC “EC Efficacy and Weight: Answers, Questions and Finding a Way Forward”. Retrieved from https://arhp.adobeconnect.com/_a707384277/p8gw6h4407g/ Trussell J, Rodríguez G, Ellertson C. New estimates of the effectiveness of the Yuzpe regimen of emergency contraception. Contraception 1998;57:363–9. Trussell J, Raymond EG. Emergency Contraception: A Last Chance to Prevent Unintended Pregnancy. November 2011. Available at http://ec.princeton.edu/questions/ec-review.pdf. von Hertzen et al. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Task Force on Postovulatory Methods of Fertility Regulation. Lancet. 1998 Aug 8;352(9126):428-33. von Hertzen H, Piaggio G, Ding J. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial. Lancet. 2002 Dec 7;360(9348):1803-10. Wilcox AJ, Weinberg CR, Baird DD. Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby. NEJM 1995;333:1517–21. Wilcox AJ, Dunson D, Baird DD. The ”fertile window” in the menstrual cycle: day specific estimates from a prospective study. BMJ 2000;18(321):1259–62. Wilcox AJ, Dunson DB, Weinberg CR, Trussell J, Baird DD. Likelihood of conception with a single act of intercourse: providing benchmark rates for assessment of postcoital contraceptives. Contraception 2001;63 (4):211 – 215. Wilkinson TA, Vargas G, Fahey N, et al. «I’ll see what I can do.»: What adolescents Experience When Requesting Emergency Contraception. J Adolesc Health 2014;54:14-19. Wood, S. (2014 May 14) The Regulatory Context [Webinar]. In ASEC “EC Efficacy and Weight: Answers, Questions and Finding a Way Forward”. Retrieved from https://arhp.adobeconnect.com/_a707384277/p8gw6h4407g/ Yuzpe AA, Lance WJ. Ethinylestradiol and DL-norgestrel as a potential contraceptive. Fertil Steril 1977;28:932–6.