BRIEFING DOCUMENT

NONPRESCRIPTION DRUGS and REPRODUCTIVE HEALTH DRUGS ADVISORY COMMITTEE
MEETING

16 DECEMBER 2003

**PLAN B^®^ (LEVONORGESTREL)**

**FOR EMERGENCY CONTRACEPTION**

**R~x~-to-OTC SWITCH**

14 November 2003

**Women's Capital Corporation**

**1990 M Street, NW**

**Suite 250**

**Washington, DC 20036**

**AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION**

TABLE OF CONTENTS

[LIST OF APPENDICES 7](#__RefHeading___Toc56513618)

[1 Introduction and Background 8](#__RefHeading___Toc56513620)

[1.1 Introduction 8](#__RefHeading___Toc56513621)

[1.2 Executive Summary 8](#__RefHeading___Toc56513622)

[1.2.1 Unintended Pregnancy 8](#__RefHeading___Toc56513623)

[1.2.2 Emergency Contraception 9](#__RefHeading___Toc56513624)

[1.2.2.1 Definition 9](#__RefHeading___Toc56513625)

[1.2.2.2 Awareness 10](#__RefHeading___Toc56513626)

[1.2.2.3 Emergency Contraception -- History
11](#__RefHeading___Toc56513627)

[1.2.2.4 Emergency Contraception -- Worldwide Experience
12](#__RefHeading___Toc56513628)

[1.2.2.5 Emergency Contraception -- Access
13](#__RefHeading___Toc56513629)

[1.2.2.6 Pharmacy Access Programs 15](#__RefHeading___Toc56513630)

[1.2.2.7 Potential Impact of Expanded Access to Emergency Contraception
16](#__RefHeading___Toc56513631)

[1.2.2.7.1 Condom Use 16](#__RefHeading___Toc56513632)

[1.2.2.7.2 Sexually Transmitted Infections (STI)
19](#__RefHeading___Toc56513633)

[1.2.2.7.3 Routine Birth Control Use 19](#__RefHeading___Toc56513634)

[1.2.3 Plan B: Post-Marketing Safety Experience
20](#__RefHeading___Toc56513635)

[1.2.3.1 Ectopic Pregnancy 25](#__RefHeading___Toc56513636)

[1.2.4 Plan B: Rx-to-OTC Switch 26](#__RefHeading___Toc56513637)

[2 CLINICAL Pharmacology of Levonorgestrel -- MECHANISM OF ACTION
28](#__RefHeading___Toc56513638)

[3 Well-Controlled, COMPARATIVE, Clinical STUDIES OF 0.75 MG
LEVONORGESTREL for Emergency Contraception (NOT SPECIFICALLY DESIGNED TO
SUPPORT AN Rx-to-OTC SWITCH) 32](#__RefHeading___Toc56513639)

[3.1 Summary of Comparative Clinical Efficacy Studies of 0.75 mg
Levonorgestrel for Emergency Contraception from NDA 21-045
32](#__RefHeading___Toc56513640)

[3.2 Controlled Studies of the Plan B Levonorgestrel Regimen for
Emergency Contraception Since the Submission of NDA 21-045
34](#__RefHeading___Toc56513641)

[4 Studies Supporting the OTC Distribution of Plan B
34](#__RefHeading___Toc56513642)

[4.1 Overview 34](#__RefHeading___Toc56513643)

[4.2 Plan B OTC Label Comprehension Study
37](#__RefHeading___Toc56513644)

[4.2.1 Overview and Study Design 37](#__RefHeading___Toc56513645)

[4.2.2 Survey Overview 39](#__RefHeading___Toc56513646)

[4.2.3 Survey Procedure 39](#__RefHeading___Toc56513647)

[4.2.4 Study Population 40](#__RefHeading___Toc56513648)

[4.2.5 Results -- All Patients 44](#__RefHeading___Toc56513649)

[4.2.5.1 Communication Objectives 44](#__RefHeading___Toc56513650)

[4.2.5.2 Communication Objective 2 46](#__RefHeading___Toc56513651)

[4.2.5.3 Communication Objective 4 47](#__RefHeading___Toc56513652)

[4.2.5.4 Communication Objective 8 49](#__RefHeading___Toc56513653)

[4.2.6 Results by Literacy Level (as assessed by the REALM test)
50](#__RefHeading___Toc56513654)

[4.2.6.1 Overview 50](#__RefHeading___Toc56513655)

[4.2.6.2 Results - Communication Objectives
53](#__RefHeading___Toc56513656)

[4.2.7 Summary and Conclusions -- Label Comprehension Study
54](#__RefHeading___Toc56513657)

[4.3 Plan B OTC Actual Use Study 56](#__RefHeading___Toc56513658)

[4.3.1 Overview and Study Design 56](#__RefHeading___Toc56513659)

[4.3.2 Study Population 60](#__RefHeading___Toc56513660)

[4.3.3 Analysis of Primary Outcome Variables of Plan B OTC Actual Use
Study 64](#__RefHeading___Toc56513661)

[4.3.3.1 Contraindicated Use 64](#__RefHeading___Toc56513662)

[4.3.3.2 Incorrect Use 65](#__RefHeading___Toc56513663)

[4.3.4 Analysis of Pregnancy During Plan B OTC Actual Use Study
66](#__RefHeading___Toc56513664)

[4.3.5 Additional Results of the Plan B OTC Actual Use Study
68](#__RefHeading___Toc56513665)

[4.3.6 Prior vs. Naïve Users 69](#__RefHeading___Toc56513666)

[4.3.7 Safety Results for the Plan B OTC Actual Use Study: Adverse
Events 70](#__RefHeading___Toc56513667)

[4.3.8 Actual Use Study: Conclusion 72](#__RefHeading___Toc56513668)

[5 benefit/risk overview of plan b as an otc emergency contraceptive
74](#__RefHeading___Toc56513669)

[5.1 Overview 74](#__RefHeading___Toc56513670)

[5.2 Risk Assessment of Plan B 74](#__RefHeading___Toc56513671)

[5.3 Benefits of OTC Plan B 76](#__RefHeading___Toc56513672)

[5.4 Discussion and Conclusions -- Risks vs. Benefits
77](#__RefHeading___Toc56513673)

[6 plan b: Convenient Access, Responsible Education Program
79](#__RefHeading___Toc56513674)

[6.1 Introduction 79](#__RefHeading___Toc56513675)

[6.2 CARE^SM^ Program Objectives 80](#__RefHeading___Toc56513676)

[6.3 Labeling/Packaging 81](#__RefHeading___Toc56513677)

[6.3.1 Core messages 82](#__RefHeading___Toc56513678)

[6.3.2 Labeling refinements 82](#__RefHeading___Toc56513679)

[6.3.3 Additional sources of information
83](#__RefHeading___Toc56513680)

[6.4 Education 83](#__RefHeading___Toc56513681)

[6.4.1 Educational Program to Healthcare Professionals.
83](#__RefHeading___Toc56513682)

[6.4.2 Educational Campaign to Consumers
84](#__RefHeading___Toc56513683)

[6.4.3 Media Coverage 85](#__RefHeading___Toc56513684)

[6.5 Distribution 85](#__RefHeading___Toc56513685)

[6.6 Monitoring 86](#__RefHeading___Toc56513686)

[6.7 Summary and Conclusions 88](#__RefHeading___Toc56513687)

[7 References 89](#__RefHeading___Toc56513688)

**LIST OF TABLES**

[Table 1: Plan B Serious Adverse Events 28 July 2002 -- 27 July 2003
22](#__RefHeading___Toc56513689)

[Table 2: Summary of Adverse Events by Body System
24](#__RefHeading___Toc56513690)

[Table 3: Well-Controlled Comparative Clinical Studies Previously
Submitted in NDA 21-045 32](#_Ref55891457)

[Table 4: Efficacy Results for Comparative Clinical Trials from
NDA 21‑045 (WHO #92908, WHO 1998b, Ho 1993)
33](#__RefHeading___Toc56513692)

[Table 5: Sponsor Studies Supporting OTC Distribution of Plan B
35](#__RefHeading___Toc56513693)

[Table 6: Socio-Demographic Characteristics of the Eligible Population
in the Plan B OTC Label Comprehension Study 41](#_Ref56425572)

[Table 7: Distribution of Eligible Subjects Seen at Mall and Clinic
Settings, by Age Group 42](#__RefHeading___Toc56513695)

[Table 8: Contraceptive History of the Eligible Population in the Plan B
OTC Label Comprehension Study 43](#__RefHeading___Toc56513696)

[Table 9: Percent of Subjects Who Understood Communication Objectives
Related to Efficacy in the Plan B OTC Label Comprehension Study
45](#__RefHeading___Toc56513697)

[Table 10: Correct Response Percentages for Questions 9, 21, 22, and 25
Making Up Communication Objective 2: Plan B is Intended as a Back Up
Method and Should Not Be Used for Regular Birth Control
46](#_Ref56447800)

[Table 11: Correct Response Percentages for Questions 10, 19, 20 and 29
Making Up Communication Objective 4: The First Pill Should Be Taken
Within 72 Hours After Intercourse 48](#__RefHeading___Toc56513699)

[Table 12: Correct Response Percentages for Question 15 Making Up
Communication Objective 8: Plan B Should Not Be Used by Women with
Unexplained Vaginal Bleeding 49](#__RefHeading___Toc56513700)

[Table 13: Socio-Demographic Characteristics of the Subjects
Administered the REALM Test in the Plan B OTC Label Comprehension Study
52](#__RefHeading___Toc56513701)

[Table 14: Percent of REALM Subgroup Who Understood Communication
Objectives Related to Efficacy in the Plan B OTC Label Comprehension
Study 53](#__RefHeading___Toc56513702)

[Table 15: Socio-Demographic Characteristics of Screened and Enrolled
Cohorts in the Actual Use Study (% of each subset)
63](#__RefHeading___Toc56513703)

[Table 16: Efficacy Results for Actual Use Study and NDA Pivotal Study
68](#__RefHeading___Toc56513704)

[Table 17: Contraceptive Methods Used Before and After Receiving Plan B
68](#__RefHeading___Toc56513705)

[Table 18: Contraindicated and Incorrect Use Among Prior and Naïve Users
of Emergency Contraception 70](#__RefHeading___Toc56513706)

[Table 19: Percent of Subjects Reporting Adverse Events in Actual Use
Study (≥ 5% reported for at least one subset) 71](#_Ref55894900)

[Table 20: Interval Between Pill Doses in Actual Use Study and NDA
Pivotal Clinical Trial 73](#__RefHeading___Toc56513708)

LIST OF FIGURES

**FIGUR**E 1: PROBABILITY OF CONCEPTION ON SPECIFIC DAYS NEAR THE DAY OF
OVULATION (WILCOX
1995)................................................................................29

[Figure 2: Instructions for Use Printed on the Outside of the Plan B OTC
Actual Use Study Label^\*^ 60](#__RefHeading___Toc56513709)

[Figure 3: Pregnancy Analysis in Actual Use Study
67](#__RefHeading___Toc56513710)

[]{#__RefHeading___Toc56513618 .anchor}LIST OF APPENDICES

**APPENDIX 1: MECHANISMS OF ACTION**

**APPENDIX 2: LABEL COMPREHENSION QUESTIONS AND QUESTIONNAIRE**

**APPENDIX 3: LABEL COMPREHENSION STUDY LABEL**

**APPENDIX 4: ACTUAL USE STUDY LABEL**

**APPENDIX 5: PROPOSED OTC LABEL**

**APPENDIX 6: CATEGORIZATION OF VERBATIM TERMS FOR LABEL COMPREHENSION
STUDY QUESTION #7**

**APPENDIX 7: PROPOSED PATIENT PACKAGE INSERT**

**APPENDIX 8: LABEL COMPREHENSION STUDY DATA TRANSCRIPTION CARD**

[]{#__RefHeading___Toc56513620 .anchor}1 Introduction and Background

[]{#__RefHeading___Toc56513621 .anchor}1.1 Introduction

This briefing document summarizes information in support of the proposed
Rx-to-over-the-counter (OTC) switch for the marketed emergency
contraceptive, Plan B^^ and describes the proposed CARE^SM^
([C]{.underline}onvenient [A]{.underline}ccess [R]{.underline}esponsible
[E]{.underline}ducation) program intended to insure the appropriate and
responsible use of Plan B. Women's Capital Corporation ("the sponsor")
proposes that expanded access to Plan B, combined with a well defined
marketing and educational program, will provide a fundamentally improved
approach to satisfying an unmet medical need that will result in the
reduction of unintended pregnancies.

Barr also contends that Plan B is an ideal OTC candidate. The
unpredictable timing of the event leading to the need for emergency
contraception, along with the following characteristics of Plan B
strongly support the switch to OTC status:

-   Early use of Plan B increases efficacy

-   Plan B has an appropriate safety profile

-   Plan B has a compelling risk/benefit assessment

-   Plan B is not used chronically.

[]{#__RefHeading___Toc56513622 .anchor}1.2 Executive Summary

[]{#__RefHeading___Toc56513623 .anchor}1.2.1 Unintended Pregnancy

There are nearly three million unintended pregnancies each year in the
United States, and about half of them end in abortion. Unintended
pregnancy remains a major public health problem, affecting women in all
reproductive age groups and socio-economic strata. Greater use of
emergency contraception (EC) could theoretically prevent up to 70% of
unintended pregnancies (Trussell 1992b). Use of emergency contraception
by American women is still relatively rare for a number of reasons,
including generally limited information that this therapeutic option
exists and restrictions on availability that limit access.

In 1994, the last year for which complete data are available, 49% of all
pregnancies in the U.S. are estimated to have been unintended and 54% of
these pregnancies ended in abortion (Henshaw 1998). Abortion rates are
highest among women who are aged 18-29, unmarried, low-income, and/or
black or Hispanic. In addition, low-income women presenting for abortion
are more likely to report problems accessing contraception (Jones
2002b). Based on 1994 data, Henshaw (1998) estimated that American women
average 1.4 unintended pregnancies over their reproductive lifetime and
that 43% of U.S. women will have an abortion by the time they reach 45
years of age (Henshaw 1998).

In addition, the incidence of contraceptive failures should not be
underestimated. More than half (53.7%) of U.S. women presenting for
elective abortion were using a method of contraception in the month they
became pregnant; of those who were not using a method, most had used
contraception in the recent past. Of note, only 1.3% reported using
emergency contraception (Jones 2002b).

[]{#__RefHeading___Toc56513624 .anchor}1.2.2 Emergency Contraception

[]{#__RefHeading___Toc56513625 .anchor}1.2.2.1 Definition

Emergency contraception is a therapy for women who have had unprotected
sexual intercourse, including sexual assault or a contraceptive failure.
Pharmacologic methods of emergency contraception have included use of
combination or progestin-only oral contraceptives, danazol, synthetic
estrogens, conjugated estrogens, and antiprogestins.

[]{#__RefHeading___Toc56513626 .anchor}1.2.2.2 Awareness

Levels of awareness regarding emergency contraception remain low, and
few women are counseled about the method in advance by their doctors. A
nationally representative survey found that just 68% of women aged 18-44
are aware that there is something they can do in the first few days
after unprotected sex to prevent pregnancy (Kaiser 2003). A 2000 survey
that probed deeper into women's "awareness" of emergency contraception
found that while 74% of women aged 18-44 surveyed claimed to have heard
of the "morning-after" pill, just 27% percent claimed to have heard of
"emergency contraceptive" pills. Furthermore, only 43% responded that
emergency contraceptive pills were available in the United States, 30%
knew that a prescription was required to obtain emergency contraception,
and only 16% understood that emergency contraceptive pills needed to be
taken within 72 hours after sexual intercourse (Kaiser 2000). Another
survey of 293 active duty members of a U.S. Air Force base found that
while 64% had heard of EC, only 15% knew the correct timeframe for use
(van Royen 2000). A product that is so time dependent cannot be used
effectively unless women are educated proactively. These studies
demonstrate that awareness and comprehensive understanding of emergency
contraception and its uses is currently inadequate to insure responsible
and effective use.

These low levels of awareness and knowledge about emergency
contraception may, in part, be due to the fact that only 25% of
gynecologists and 14% of general practice physicians reported that they
talk about this method "always" or "most" of the time (Kaiser 2003a).
This may be due to physicians being too busy to discuss an event that
may or may not be relevant for any given patient. The lack of knowledge
about emergency contraception is likely to result in a number of
preventable unintended pregnancies, as a recent survey of U.S. women
(n=10,683 usable questionnaires) obtaining abortions in 2000-2001 found
that just 1.3% of women reported taking emergency contraceptive pills to
prevent the pregnancy (Jones 2002b). Despite the reported rates of
unintended pregnancy, another survey from earlier this year found that
only 6% of women aged 18-44 reported ever having used emergency
contraception (Kaiser 2003b).

[]{#__RefHeading___Toc56513627 .anchor}1.2.2.3 Emergency Contraception
-- History

Over the last several decades a variety of approaches to emergency
contraception have been evaluated, including high-doses of estrogen,
estrogen combined with progestin, progestin alone, antiprogestational
agents and intrauterine devices (IUDs) (Van Look 1993; Glasier 1997).
Ovral*^®^* (0.5 mg norgestrel/0.05 mg ethinyl estradiol), a high-dose
combined oral contraceptive approved for use in 1968, was a standard
product used for emergency contraception in the U.S. from the mid-1970s.
Dosed as 2 tablets (total dose: 1.0 mg norgestrel/0.1 mg ethinyl
estradiol) within 72 hours of unprotected sex, followed by another 2
tablets 12 hours after the first dose (total dose: 1.0 mg norgestrel/0.1
mg ethinyl estradiol) (generally referred to as the Yuzpe regimen after
its Canadian developer), it was declared a safe and effective regimen by
the FDA in 1997. A combination product based on the Yuzpe regimen,
Preven^®^, was approved by the FDA in 1998. To date, all approved
emergency contraceptive products are available by prescription only.

Beginning in the late 1980s, investigators recognized the potential of
levonorgestrel as an emergency contraceptive in place of the standard
Yuzpe regimen of combined high-dose oral contraceptives (containing
estrogen and progestin). Levonorgestrel has a long history of use in
combination oral contraceptives and there are substantial data to
support the drug's efficacy in pregnancy prevention, including the
efficacy of elevated doses used postcoitally. Using levonorgestrel 0.75
mg tablets already marketed by Gedeon Richter, Ltd., the World Health
Organization (WHO) sponsored two well-controlled studies of
levonorgestrel for emergency contraception, both of which were published
(Ho 1993, WHO 1998b). The first of these studies was a single-center,
randomized trial of levonorgestrel compared with the Yuzpe regimen in
women requesting emergency contraception within 48 hours of unprotected
intercourse. In this study, levonorgestrel was found to be as effective
in preventing pregnancy as the Yuzpe regimen.

WHO subsequently conducted a multi-center, randomized, double-blind
study (WHO #92908) in order to confirm and expand the findings of Ho *et
al*. (1993). In this study conducted in 14 countries, 1,998 women from a
wide variety of racial and ethnic groups participated. Two separate
doses of levonorgestrel 0.75 mg (taken 12 hours apart within 72 hours of
unprotected sex) showed greater efficacy when compared with the Yuzpe
regimen. The results indicated that Plan B is 89% effective if used as
labeled within 72 hours of unprotected sex. Plan B reduced the risk of
pregnancy following a single act of mid-cycle unprotected sexual
intercourse from 8%, on average, to 1.1%. The regimen was demonstrated
to be more effective if treatment is initiated soon after unprotected
sex than if treatment is delayed. Taken within 24 hours of coitus, the
regimen reduced the risk of pregnancy by 95%, from about 8% to 0.4%.

Plan B was approved by the U.S. Food and Drug Administration (FDA) in
1999 as a prescription product indicated for use following a
contraceptive accident, failure to use a regular contraceptive method
correctly or sexual intercourse without contraception, including cases
of sexual assault.

[]{#__RefHeading___Toc56513628 .anchor}1.2.2.4 Emergency Contraception
-- Worldwide Experience

Levonorgestrel has a 40-year history of safe use in combined and
progestin-only contraceptives. In addition, there is a 30-year history
of clinical research on elevated doses of levonorgestrel for postcoital
contraception and 20 years of foreign marketing experience for the 0.75
mg tablet manufactured by Gedeon Richter Ltd., which provide ample
evidence of the safety and efficacy of 0.75 mg levonorgestrel tablets in
postcoital pregnancy prevention.

The extensive body of efficacy and safety data, from multiple studies by
many different investigators, and covering a diverse population of
women, provide considerable reassurance that Plan B should remain highly
safe and effective in an OTC environment. The levonorgestrel regimen for
emergency contraception is currently approved in 101 countries. In 33 of
these countries it is currently sold without a prescription, by
pharmacists, or OTC. In Israel, Norway and Sweden, levonorgestrol is
available OTC. In 30 countries, including the UK and France, it is
available directly from a pharmacist without a prescription.[^1] Of
those countries where Plan B is currently sold without a prescription,
the UK, Finland and Switzerland provide access to Plan B with age
restrictions. Clinical trials, medical literature and post-marketing
surveillance by regulatory agencies indicate no clinically significant
safety problems. An evaluation of international post-marketing adverse
events also shows that "real-life" usage of emergency contraception does
not pose any safety concerns.

[]{#__RefHeading___Toc56513629 .anchor}1.2.2.5 Emergency Contraception
-- Access

Since the efficacy of emergency contraception has been found to be
significantly affected by the amount of time between the unprotected
sex-act and using emergency contraception, rapid access to the method is
of critical importance to maximize efficacy. A pooling of the results
for the Yuzpe regimen (estrogen and progestin) of emergency
contraception combined with Plan B found that each 12 hours of delay
reduces efficacy by about 50% (p=0.02) (Piaggio 1999). Treatment is
completely ineffective once the process of implantation of a fertilized
egg is underway, a process that begins within five to seven days after
coitus (Grimes 2001, Raman-Wilms 1995, Bracken 1990).

The majority of American women who must seek a prescription from a
private physician and then fill it at a pharmacy face even greater
barriers to timely use than do clinic populations where emergency
contraception is well understood and provided at the time of the visit.
Even in the hospital and clinic setting, Shawe *et al.* (2001) found
that only 4% of women accessing the method at a healthcare facility
obtained it in the first 12 hours and only 37% did so in 12-24 hours. A
review of eight other studies found that only 27% to 61% of women
accessed the method within 24 hours, 23% to 33% in 24 to 48 hours, and
10% to 25% in 49 to 72 hours (Ashok 2002, Arowojolu 2002, WHO 2002,
Roizen 2001, Nanthakumaran 1998, Tydén 1998, Evans 1996, Roberts 1995).
Highlighting problems with access, a recent study from University of
California, San Francisco (UCSF) found that 14% of 663 subjects reported
wanting to use emergency contraception in the past but not doing so
because of: inconvenience (17%), difficulty with the 72-hour limit
(11%), the clinic was closed (7%), they did not know where to go (9%),
and other reasons (15%) (UCSF 2003b).

Another aspect reflecting a logistical barrier to obtaining EC was
recently published by Espey et al. An assessment was performed to
determine the immediate availability of prescription emergency
contraception (Plan B and Preven) at pharmacies in Albuquerque, New
Mexico. A prescription for either Plan B or Preven was presented at 89
pharmacies and found that neither EC was immediately available at 89% of
the pharmacies included in the study. At those pharmacies where EC was
not immediately available, only 53% predicted that they could obtain the
product for the patient within 24 hours. The authors concluded that
"lack of availability at the pharmacy constitutes a major barrier to
emergency contraception access." (Espey, 2003) Thus, any program
designed to maximize the efficacy of Plan B must include education about
appropriate use of Plan B, education about where and how to obtain Plan
B and finally a mechanism to insure availability of Plan B at the
pharmacy level.

[]{#__RefHeading___Toc56513630 .anchor}1.2.2.6 Pharmacy Access Programs

While emergency contraceptive pills are still prescription products in
the United States, there are currently five states in the U.S. where a
woman can walk in to a pharmacy and obtain emergency contraceptive pills
without an advance prescription from a prescriber. These five states are
Alaska, California, Hawaii, New Mexico, and Washington State. The
changes made by each state relate to their existing pharmacy practice
laws. Some states required legislative change, others required
regulatory change, and one state, Washington, needed no formal change in
law, but needed to bring about institutional acceptance for this new
practice.

 

Pharmacy access to emergency contraception was initiated in 1997 in the
United States:

-   1997 - Washington State initiated its pilot program, which became a
    self-sustaining program just two years later.

-   2000 - California initiated a pilot program with 70 pharmacies.

-   2002 - California legislation took effect allowing a statewide
    effort; Alaska approved its first collaborative protocols allowing
    pharmacists to dispense emergency contraception.

-   2003 - New Mexico approved a statewide protocol to allow for
    pharmacy access; Hawaii passed legislation that will allow women to
    access emergency contraception directly from a pharmacist as soon as
    a standardized protocol is developed.

 

A preliminary assessment of the first two months of the pharmacy access
program in Washington State found that pharmacy access was key to
greater utilization of emergency contraception: 42% of women (n=129)
responding to a mail-in questionnaire indicated that without pharmacy
access they would simply have waited to see if they became pregnant, and
16% said they did not know what they would have done (Wells 1998); among
adolescents (aged 15-21, n=126), 22% would have waited to see if they
got pregnant and 20% did not know what they would have done (Sucato
2001).

 

Additional data on adolescents accessing the services (n=126, aged
15-21), found that extended accessible hours to the regimen were
utilized, as 45% obtained emergency contraception on the evening and/or
the weekend. In addition, although prior use of the method was common,
repeated prior use was not: 32% had used emergency contraception 1 or
more prior times, with 10% using it 2 or more prior times, and just 6%
using it 3 or more prior times (Sucato 2001).

 

In addition, adolescents did not represent a disproportionate share of
consumers accessing emergency contraception directly from a pharmacist
in Washington State, as the mean age of women seeking services was 24.5
years, with only 13% under 18 years of age. Timely access was met, as a
review of 991 pharmacy records revealed that 70% of women received
emergency contraception within 1 day of unprotected intercourse. It
appears that barriers were also removed, which likely contributed to the
timely access, as 20% of respondents reported that they went to a
pharmacist because their physician's office was closed, 7% reported that
their regular clinic or physician didn't prescribe emergency
contraception, and 14.8% reported that they had no regular clinic or
physician (Downing 2000).

[]{#__RefHeading___Toc56513631 .anchor}1.2.2.7 Potential Impact of
Expanded Access to Emergency Contraception

[]{#__RefHeading___Toc56513632 .anchor}1.2.2.7.1 Condom Use

Easier access to emergency contraception does not appear to undermine
condom use. Easier access to emergency contraception as a backup (i.e.,
in the event of condom breakage, slippage, or leakage) may, in fact,
allow more women to rely on condoms for both birth control and disease
prevention (WCC/FHI 2002, UCSF 2003b, Raine 2000).

** **

A number of studies provide information about the effects of emergency
contraception on condom use. In the Plan B^®^ OTC Actual Use Study,
10.3% of subjects who reported no condom use before admission were using
condoms at follow-up, compared to only 4.7% of condom users who had
stopped using the method (WCC/FHI 2002). This result is consistent with
the literature. At the three‑month follow-up of 39 women given a
Preven^®^ emergency contraception kit to keep at home, 39% of those who
had not reported condom use at last intercourse during enrollment did
report condom use at last intercourse at the time of follow-up. Just 15%
of those who had used a condom at last intercourse at enrollment were
not using a condom after three months in the study, suggesting a net
gain of 24% in condom use (Roye 2002, Roye 2001). In the 1994--1996
study in Scotland by Glasier *et al.* (1998) comparing women who
received an off-label regimen of emergency contraception in advance with
those who had to obtain it from the clinic, there was no difference
between the two groups with respect to the use of condoms. A subsequent
study of advanced provision by Raine *et al.* (2000), also using an
off-label regimen, showed similar results among low-income minority
adolescents and young adults in San Francisco. There was no difference
between the advanced provision and clinic access groups with respect to
the consistency of condom use at the four-month follow-up.

>  

In the UCSF Emergency Contraception Access Study of Plan B (UCSF 2003b),
the advanced provision and pharmacy access groups each showed a
statistically significant decrease in rates of condom use at last sex
from baseline to follow-up (p\<0.007 and p\<0.001, respectively), while
the clinic access group remained relatively consistent over time
(p\<0.651). In this study, young women at high risk of unintended
pregnancy and STI acquisition were given access to three free packages
of Plan B. Condom use at last intercourse was lightly lower in the
advance provision group (48.9%) and pharmacy access group (50.6%) than
in the clinic access group (55.7%) (p\<0.097). No differences were
shown, however, in frequency of condom use or current use of condoms.
Primary and secondary endpoints were compared for adolescents
(15--17 years) and young adults (18--24 years). At follow-up interviews
six months (to a year) after enrollment, there were no significant
differences between the two age groups in condom use since entering the
study (p\<0.519), condom use at last intercourse (p\<0.933) or current
use of condoms (p\<0.938). The impact on condom use was mixed, but
adolescents appeared no more likely to modify their condom use than
young adults. In the study by Belzer *et al.* (2003) of adolescent
mothers aged 14-20, also conducted with Plan B, there was no difference
in condom use between subjects given Plan B in advance or those who had
to return to a clinic setting to receive the product.

These and other studies of advanced provision, in which women
self‑diagnosed their need for emergency contraception and used it
without medical oversight---often many months after receiving
counseling---provide further support that Plan B can be used safely,
effectively and appropriately without medical supervision. As noted
above, the UCSF results (UCSF 2003b) could suggest that in particularly
vulnerable populations prone to risky sexual behavior, easy cost-free
access to emergency contraception, through advanced provision or free
pharmacy access may increase slightly some types of risk-taking.

It cannot be assumed that OTC sale of Plan B in retail pharmacies would
have a similar impact, since users would be required to pay for the
product. It is important to note that when compared to routine use of
condoms or even oral contraceptives, Plan B is a very expensive form of
"routine" birth control. The cost of repetitive use of Plan B is in and
of itself a deterrent to repeated use for most of the population. The
small decreases in consistent condom use observed in the recent UCSF
Emergency Contraception Access Study (2003b) were not observed in the
Glasier *et al.* (1998), Raine *et al.* (2000), or Belzer *et al.*
(2003) studies. The explanation may be that in the Glasier, Raine, and
Belzer studies, subjects were given only one course of treatment in
advance, while in the UCSF study subjects were given three packages of
Plan B in advance or a card allowing them access to up to three free
packages at a pharmacy. Plan B is packaged in single-use packages. Women
will need to consider cost when making their contraceptive choices.
Finally, the CARE^SM^ program will actively encourage the use of routine
birth control through the distribution of written materials to consumers
as well as a hotline and website providing responsible and accurate
information.

[]{#__RefHeading___Toc56513633 .anchor}1.2.2.7.2 Sexually Transmitted
Infections (STI)

In the UCSF Emergency Contraception Access Study (2003b) comparing
advanced provision, pharmacy access and standard clinic access, there
was no evidence of a difference in the acquisition of an STI during the
study among the three groups. It is important to note that subjects were
given access to three free packages of Plan B. In the study population
as a whole, 22.3% of participants had a history of STIs. During the
study, a total of 156 participants (16.7%) acquired an STI
(self-reported [or]{.underline} by laboratory tests), including: 47
(14.9%) in the advance provision group, 58 (18.5%) in the pharmacy
access group and 51 (16.7%) in the clinic access group. The differences
were not statistically significant. There were no differences among the
three groups when controlling for baseline history of STIs (p\<0.427).
When primary and secondary endpoints were compared for adolescents
(15-17 years) and young adults (18-24 years) at follow-up interviews six
months (to a year) after enrollment, there were no significant
differences between the two age groups in sexually transmitted disease
acquisition (p\<0.719).

[]{#__RefHeading___Toc56513634 .anchor}1.2.2.7.3 Routine Birth Control
Use

Studies also show that women with access to EC typically do not abandon
regular contraception or use their chosen method less consistently. A
growing body of literature suggests that women with easier access to EC
are more likely to use EC following an occasional episode of unprotected
sex than women who must visit a clinic or doctor's office for a
prescription (Glasier 1998c, Raine 2000, Belzer 2003, Jackson 2003,
Ellertson 2001a), but they are generally not more likely to abandon
regular contraception (Belzer 2003, Jackson 2003, UCSF 2003b). Women who
use EC following a pregnancy scare may actually be more likely to use an
effective ongoing contraceptive method afterwards (Riain 1998, Rowlands
2000). A number of studies also provided evidence that advanced
provision did not increase the incidence of unprotected sex (Raine 2000,
Belzer 2003, Jackson 2003).

The availability of Plan B in community pharmacies along with an
appropriate and responsible education program will help raise awareness
of emergency contraception and encourage its appropriate use. Once women
are educated about emergency contraception in the context of providing a
clear understanding of how it fits into a responsible contraceptive
strategy, eliminating the need for a prescription provides for more
direct and timely access in the event of a contraceptive emergency.
Thus, the change to OTC availability of Plan B should not encourage the
inappropriate use of this product but with responsibly designed
educational and marketing programs, will maximize efficacy and thereby
decrease the incidence of unintended pregnancies and potentially
abortion.

[]{#__RefHeading___Toc56513635 .anchor}1.2.3 Plan B: Post-Marketing
Safety Experience

Plan B has been marketed as a prescription drug product in the U.S.
since 1999. During the most recent reporting period, 28 July 2002 to 27
July 2003, WCC received 216 initial post-marketing Adverse Drug
Experience (ADE) reports containing 327 adverse events. No deaths were
reported. These 216 reports included 191 nonserious and/or labeled
events from the U.S. and 25 serious adverse events from the U.S. and
Chemical Works of Gedeon Richter, Ltd. (Gedeon Richter), which markets
levonorgestrel tablets in 40 countries worldwide, the Canadian Adverse
Drug Reaction Monitoring Program (CADRMP), and the published literature.

Table 1 lists the serious adverse event reports received during the
reporting period. The 25 serious adverse event reports included 35
adverse events. Although the possibility of ectopic pregnancy is
described under the warning section in the labeling for Plan B, ectopic
pregnancies were considered serious adverse events and were reported to
the FDA.

[]{#__RefHeading___Toc56513689 .anchor}Table 1: Plan B Serious Adverse
Events 28 July 2002 -- 27 July 2003

  ---------------------- -------------------------- ----------------------
  **Event Description**  **Preferred Term(s)**      **Date Submitted**

  Ectopic pregnancy      Ectopic pregnancy          9/11/2002

  Benign dermoid cyst,   Benign ovarian germ cell   9/11/2002
  Ectopic pregnancy      teratoma, Ectopic          
                         pregnancy                  

  Ectopic pregnancy      Ectopic pregnancy          9/11/2002

  Ectopic pregnancy      Ectopic pregnancy          10/9/2002

  Ectopic pregnancy      Ectopic pregnancy          11/12/2002

  Ectopic pregnancy      Ectopic pregnancy          11/12/2002

  Congenital anomaly     Congenital anomaly         12/9/2002

  Itching, rash, hives   Itching, rash, hives       2/19/2003

  Ectopic pregnancy      Ectopic pregnancy          3/6/2003

  Unintended pregnancy,  Unintended pregnancy,      3/6/2003
  spontaneous abortion   abortion                   

  Ectopic pregnancy      Ectopic pregnancy          3/6/2003

  Ectopic pregnancy      Ectopic pregnancy          3/18/2003

  Fetus detached from    Abruptio placentae         4/2/2003
  uterine wall                                      

  Unintended pregnancy   Unintened pregnancy        4/16/2003

  Ectopic pregnancy       Ectopic pregnancy         4/16/2003

  Unintended pregnancy,   Unintended pregnancy,     5/6/2003
  hospitalization after  antepartum hemorrhage,     
  spot bleeding, induced induced abortion           
  abortion                                          

  Ruptured tubal          Ruptured tubal pregnancy  5/21/2003
  pregnancy                                         

  Right ruptured tubal   Ruptured tubal pregnancy,  5/21/2003
  pregnancy              vaginal bleeding           

  Possibility of a        Abdominal pain, nausea,   5/21/2003
  right-sided ectopic    right ectopic pregnancy    
  pregnancy                                         

  Unintended pregnancy,   Unintended pregnancy,     5/21/2003
  miscarriage            missed spontaneous         
                         abortion                   

  Ectopic pregnancy,      Ectopic pregnancy         7/11/2003
  ovarian cystectomy                                

  Unintended pregnancy    Unintended pregnancy      5/21/2003

  Unintended pregnancy,  Unintended pregnancy,      5/28/2003
  premature rupture of   caesarean section          
  membrane                                          

  Ectopic pregnancy      Ectopic pregnancy,         5/28/2003
                         laparotomy, salpingectomy  

  Ectopic pregnancy      Ectopic pregnancy          7/14/2003
  ---------------------- -------------------------- ----------------------

The adverse events received by WCC (362 events in 216 reports) and all
the serious adverse events (numbering 35 events in 25 reports) are
summarized in the following table by WCC Preferred term (Table 2).

[]{#__RefHeading___Toc56513690 .anchor}Table 2: Summary of Adverse
Events by Body System

  --------------------------- --------------- -------------- ---------------
  **Preferred Term**          **Non-serious                  **15-Day Alert
                              Events**                       Events**

                              **Number of     **Percentage   
                              Reported        of Total       
                              Events**        Events**       

  **Body as a Whole**                                        

  Fatigue/asthenia            15              4.6            

  **Cardiovascular System**                                  

  Irregular rapid pulse       1               0.3            

  **Gastrointestinal System**                                

  Nausea                      34              10.4           1

  Vomiting                    8               2.5            

  Diarrhea/loose stools       7               2.1            

  Bloating/water retention    5               1.5            

  Stomachache                 2               0.6            

  Metallic taste in mouth     1               0.3            

  Appetite loss               1               0.3            

  **Neurological System**                                    

  Headache                    11              3.4            

  Dizziness/lightheaded       9               2.8            

  Emotional changes           2               0.6            

  Irritability                1               0.3            

  Shakiness in hands          1               0.3            

  Twitching in right eye      1               0.3            

  Blurred vision              1               0.3            

  **Respiratory System**                                     

  Labored breathing           1               0.3            

  Return of asthma symptoms   1               0.3            

  **Dermatological**                                         

  Rash/hives                  3               0.9            1

  Acne                        1               0.3            

  Itching                     3               0.9            1

  **Musculoskeletal System**                                 

  Back pain                   2               0.6            

  Mylagia                     1               0.3            

  **Genitourinary System**                                   

  Menstrual irregularities    98              30.0           1

  Abdominal pain/cramping     47              14.4           1

  Unintended pregnancy        30              9.2            6

  **Preferred Term**          **Nonserious                   **15-Day Alert
                              Events**                       Events**

                              **Number of     **Percentage   
                              Reported        of Total       
                              Events**        Events**       

  Breast tenderness/pain      22              6.7            

  Ectopic pregnancy                                          16

  Vaginal discharge           5               1.5            

  Vaginal pain                2               0.6            

  Abortion                                                   3

  Galoctorrhea                1               0.3            

  Urinary frequency           3               0.9            

  Hematuria                   2               0.6            

  Urinary urgency             2               0.6            

  Congenital anomaly                                         2

  Ovarian cyst                2               0.6            1

  Dysuria                     1               0.3            

  Abruptio placentae                                         1

  Antepartum hemorrhage                                      1

  **TOTAL:**                  **327**                        **35**
  --------------------------- --------------- -------------- ---------------

Post-marketing pharmacovigilance has not identified any unexpected
adverse events. Most adverse events reported were not life-threatening.
The only serious adverse event reported multiple times was ectopic
pregnancy. Ectopic pregnancy is included in the warning section of the
label but is not thought to be associated with the use of Plan B.

[]{#__RefHeading___Toc56513636 .anchor}1.2.3.1 Ectopic Pregnancy

The incidence of ectopic pregnancy in the United States general
population is 2% of all pregnancies. In routine (i.e., daily) users of
progestin-only oral contraceptives, up to 10% of the pregnancies that
occur are ectopic. This incidence is higher than with most other
contraceptive methods (McCann and Potter 1994). Although the mechanism
is uncertain, it may be due to the decreased activity of the fallopian
tube cilia and changes in tubal motility that interfere with the
transport of the ovum.

There does not appear to be an increased risk of ectopic pregnancy with
use of\
Plan B. In clinical studies including more than 11,000 women who used
Plan B for postcoital contraception there were 3 reported ectopic
pregnancies of a total 198 pregnancies giving an ectopic pregnancy rate
of 1.5%.

Additional reports of ectopic pregnancy with use of Plan B have been
received from the post-marketing setting. The number of ectopic
pregnancies is high compared to the number of unintended pregnancies
reported to pharmacovigilance authorities. This is probably due to less
reporting of unintended pregnancy because it is not usually considered a
serious or unexpected adverse event, but a product failure. Ectopic
pregnancies are much more likely to be reported than intrauterine
pregnancies, since they are abnormal and thus more likely to be
considered an adverse event.

These data suggest no increased risk of ectopic pregnancy for
levonorgestrel emergency contraception. In addition, the proposed Plan B
OTC label cautions women to be alert for symptoms of associated with
ectopic pregnancy and to see their healthcare professional should any of
these symptoms arise.

In summary, post-marketing surveillance data support the safety and
efficacy of Plan B as a prescription drug product. Most adverse events
were nonserious and not life-threatening. Based on exposure, the
incidence of ectopic pregnancy should not be expected to exceed that
seen in the general population. Based on existing safety data, the
change from prescription to OTC availability for Plan B is not
anticipated to have an adverse impact on the safety profile.

[]{#__RefHeading___Toc56513637 .anchor}1.2.4 Plan B: Rx-to-OTC Switch

On 16 April 2003, Women's Capital Corporation (WCC) submitted a
Supplemental New Drug Application (sNDA) to change the status of Plan B
from prescription only to OTC. Two studies to support an Rx-to-OTC
switch were developed through a highly interactive process with the FDA
OTC Division. The OTC Label Comprehension Study was undertaken to
evaluate the ability of women to understand the instructions for use
after reviewing a prototype OTC label (Appendix 3). Since the dose and
dosing regimen in the sNDA proposed labeling are identical to the
approved prescription-only labeling, the goal of this study was to
determine whether the proposed OTC labeling could be understood by the
patient without medical screening or counseling from a healthcare
professional.

The second study supporting the Rx-to-OTC sNDA was the OTC Actual Use
Study, designed to provide information on the ability of the target
population to self-select and appropriately use Plan B when labeled for
OTC distribution. The primary objective was to estimate the frequency of
contraindicated and incorrect uses of Plan B when dispensed under
simulated OTC conditions. Repeat and prior use of emergency
contraception, the impact of emergency contraception on regular
contraceptive use, pregnancy and pregnancy outcome, and reports of
adverse events were also evaluated in this study.

These two studies conducted to support the R~x~-to-OTC switch provide
substantial evidence that women (1) can self-diagnose their need for
emergency contraception; (2) can understand the directions for use of an
emergency contraceptive product; and (3) can self-administer the product
in a manner likely to be safe and efficacious without medical screening
or counseling from a healthcare professional\
(see Section 4).

Plan B's Rx-to-OTC switch is supported by leading U.S. medical
organizations who agree that the current prescription requirement
creates a major barrier to timely access and who agree that the
levonorgestrel regimen is safe, easy to use and, if used quickly, highly
effective in preventing pregnancy. In addition, there is no evidence
that levonorgestrel would harm a pregnant woman or a developing fetus if
the product is taken accidentally during early pregnancy (Grimes 2001,
Raman-Wilms 1995, Bracken 1990). A number of organizations have passed
resolutions in support of OTC status, including the American College of
Obstetricians and Gynecologists, the American Academy of Family
Physicians, the American College of Nurse-Midwives, the American Medical
Association, the Association of Reproductive Health Professionals, the
National Medical Association, and Physicians for Reproductive Choice and
Health. In addition, over 70 organizations have petitioned FDA to remove
the prescription requirement for emergency contraception (CRLP 2001).

Barr proposes to support the OTC distribution of Plan B with the
CARE^SM^ Program ([C]{.underline}onvenient [A]{.underline}vailability
[R]{.underline}esponsible [E]{.underline}ducation, see Section 6). This
program focuses on education at all levels in concert with increased
availability at the pharmacy level. This program has several major
components intended to increase awareness about the appropriate and
responsible use of Plan B, while insuring availability of Plan B at the
pharmacy. Education programs will be targeted to healthcare providers
and consumers through their healthcare provider. Barr recognizes that in
order to responsibly sell and market this product, it is essential to
provide education and increase availability without encouraging risky
behavior. Thus, the intent of the CARE^SM^ program is to insure that
women are aware of Plan B, know how and when to use it, and understand
how to easily obtain it in the most expeditious manner. More detail is
provided on the CARE^SM^ program in Section 6.

[]{#__RefHeading___Toc56513638 .anchor}2 CLINICAL Pharmacology of
Levonorgestrel -- MECHANISM OF ACTION

It is likely that levonorgestrel emergency contraception, like other
systemic methods of contraception, works in several different ways,
depending on the cycle day of unprotected sex and the cycle day of
treatment (Croxatto 2002d, see Appendix 1). The only mechanism of action
that has been clearly demonstrated to prevent pregnancy is the impact of
emergency contraception on the ovulatory process (Croxatto 2002d, Müller
2002, Croxatto 2002b, Trussell 2002, 2003c). In addition to suppressing
or delaying ovulation, the drug may compromise the ovulatory process to
the degree that fertilization is not possible, or interfere with sperm
migration and function (Croxatto 2002d, Yeung 2002).

There are only six fertile days in the menstrual cycle -- that is, days
in which an act of sexual intercourse can give rise to pregnancy. These
are the day of ovulation and the five preceding days (Figure 1, Wilcox
1995). Thus, in most cases spermatozoa spend one to five days in the
female genital tract before encountering the ovum. This interval
provides an opportunity to interfere with the migration and function of
the sperm and/or with the process of ovulation. Emergency contraceptive
pills may prevent the encounter of spermatozoa with the ovum; and, even
if the two gametes do come in contact, fertilization may not proceed to
completion. (Croxatto,
2002d)![](media/image1.wmf){width="2.8715277777777777in"
height="1.9215277777777777in"}

In human beings, fertilization is not very efficient: in ideal
circumstances, when intercourse takes place during the most fertile
days, the chance that fertilization will take place does not exceed 50%.
On average, in couples not using any method of birth control, the chance
of conception during any one cycle is approximately\
25-30%. Even with daily intercourse, most ovulatory menstrual cycles may
be incapable of producing a conception (Wilcox 1995), as other factors
(such as age) apparently have a strong role in determining fertility. It
is plausible that even minor alterations in reproductive processes will
greatly lessen the likelihood of pregnancy. This possibility has been
explored experimentally in a few studies, and emergency contraceptive
pills have been shown to interfere with pre-fertilization events
(Croxatto 2002d).

The only mechanism of action that has been clearly demonstrated to
prevent pregnancy is the impact of emergency contraception on the
ovulatory process (Croxatto 2002d, Müller 2002, Croxatto 2002b, Trussell
2002, 2003c). Current understanding of ovulation is that a mid-cycle
surge of luteinizing hormone from the pituitary acts on a follicle in
the ovary, setting into motion a series of coordinated events, and
resulting in release of an oocyte and transformation of the empty
follicle into the corpus luteum. When the normal luteinizing hormone
surge or any of the subsequent events is altered, the result can be
ovulatory dysfunction and compromised fertilization. Depending on the
timing of the administration relative to the luteinizing hormone surge,
levonorgestrel inhibits or postpones this luteinizing hormone surge,
inhibits or postpones rupture of the follicle, interferes with the
formation of the corpus luteum, or has no effect on these indices.
(Croxatto 2002d)

Through the above mechanisms, levonorgestrel emergency contraception
pills given during the preovulatory phase of the menstrual cycle have
the capacity to interfere with the ovulatory process by suppressing or
delaying ovulation. Additionally, even if ovulation does occur, the drug
may compromise the ovulatory process to the degree that fertilization is
not possible. Another mechanism by which levonorgestrel may work is by
interfering with sperm migration and function. Interference with the
fertilization process has not been directly demonstrated for
levonorgestrel emergency contraception (Croxatto 2002d, Yeung 2002).

Sperm migration in women occurs in two phases. In the first phase, a few
minutes after insemination some spermatozoa, aided by propulsive
contractions of the genital tract, reach the fallopian tube. In the
second phase, over several days, spermatozoa that have been stored in
the crypts of the uterine cervix migrate in successive cohorts towards
the fallopian tube. Only those from the second phase have the ability to
fertilize. Administration of levonorgestrel 3-10 hours after sexual
intercourse has been shown to affect sperm migration between 3 and 9
hours after treatment. It reduced the number of spermatozoa recovered
from the uterine cavity, increased the pH of the uterine fluid (which
immobilized spermatozoa), and increased the viscosity of cervical mucus
(which impeded further passage of sperm cells into the uterine cavity)
(Kesserii 1974). Although the dose of levonorgestrel in this study was
only 57% of the current levonorgestrel dosage, these results are highly
relevant to the actions of levonorgestrel when administered as an
emergency contraceptive. If ovulation occurs after a woman has taken
levonorgestrel, interference with the sustained phase of sperm migration
could well reduce or eliminate the probability of fertilization.
(Croxatto 2002d)

Levonorgestrel alters the endometrium to varying degrees depending on
dose. The impact of these endometrial changes on implantation is
unclear. There is little direct evidence that prevention of implantation
is a mechanism of action for levonorgestrel emergency contraception
(Croxatto 2002d, Ugocsai 2002, Kahlenborn 2002). Alterations in
endometrial receptivity that could interfere with implantation have been
investigated, but only indirectly. Some studies have found alterations
in endometrial morphology or in the expression of certain
progesterone-dependent molecules. Whether such changes have a
deleterious effect on endometrial receptivity is questionable. Other
studies have found either negligible alterations or none, and in the
case of levonorgestrel, existing evidence does not support the
hypothesis that it alters endometrial receptivity or impedes
implantation. (Croxatto 2002d)

Overall, the available data suggest that the primary mechanisms of
action likely interfere with the ovulatory process. Since most of the
risk of pregnancy is concentrated in the days leading up to and
including the day of ovulation and since a direct effect on the process
of ovulation has been demonstrated, it is likely that Plan B works
primarily and perhaps exclusively prior to fertilization. The fact that
emergency contraception is more effective the sooner it is used would
also argue against important post-fertilization modes of action
(Trussell 2003c, Croxatto 2002d).

[]{#__RefHeading___Toc56513639 .anchor}3 Well-Controlled, COMPARATIVE,
Clinical STUDIES OF 0.75 MG LEVONORGESTREL for Emergency Contraception
(NOT SPECIFICALLY DESIGNED TO SUPPORT AN Rx-to-OTC SWITCH)

[]{#__RefHeading___Toc56513640 .anchor}3.1 Summary of Comparative
Clinical Efficacy Studies of 0.75 mg Levonorgestrel for Emergency
Contraception from NDA 21-045

Two well-controlled studies were presented and summarized in NDA 21-045
(approved in July 1999). These randomized trials evaluated a two-dose
regimen of levonorgestrel 0.75 mg tablets compared to the older Yuzpe
regimen of combined high-dose oral contraceptives (Table 3) --- the
standard for emergency contraception at the time.

[]{#_Ref55891457 .anchor}

Table 3: Well-Controlled Comparative Clinical Studies Previously
Submitted in NDA 21-045

+------------+----------------------------+-----------------+---------+
| **Study**  | **Regimens**               | **Number of     | **Des   |
|            |                            | Subjects        | ign\*** |
|            |                            | Included in     |         |
|            |                            | Analysis**      |         |
+------------+----------------------------+-----------------+---------+
| WHO #92908 | > \- Two doses of 0.75 mg  | 976             | AC, DB, |
|            | > LNG 12 h apart           |                 | MC, R   |
| (WHO       | >                          | 979             |         |
| 1998b)     | > \- Two doses of EE 0.05  |                 |         |
|            | > mg + NG 0.50 mg 12 h     |                 |         |
|            | > apart (Yuzpe)            |                 |         |
+------------+----------------------------+-----------------+---------+
| Ho *et     | > \- Two doses of 0.75 mg  | 410             | AC, R,  |
| al.*       | > LNG 12 h apart           |                 | SC      |
|            | >                          | 424             |         |
| \(1993\)   | > \- Two doses of EE 0.05  |                 |         |
|            | > mg + NG 0.50 mg 12 h     |                 |         |
|            | > apart (Yuzpe)            |                 |         |
+------------+----------------------------+-----------------+---------+

> *\* Abbreviations used in this table: AC=Active Control,
> DB=Double-Blind, EE= Ethinyl Estradiol, LNG=Levonorgestrel, MC=
> Multi-Center, NG=Norgestrol, R=Randomized, SC=Single-Center*

The pivotal Plan B clinical study for NDA 21-045 was designed,
coordinated, monitored and analyzed by the WHO Special Programme of
Research, Development and Research Training in Human Reproduction (WHO
#92908, WHO 1998b). It was conducted between 1995 and 1997 at 21
clinical sites in 14 countries on five continents. The earlier Ho *et
al.* (1993) study was conducted at the Family Planning Association of
Hong Kong.

In the pivotal multi-center study, 31 women (3.2% of the efficacy
population) became pregnant in the Yuzpe group and 11 (1.1% of the
efficacy population) became pregnant in the levonorgestrel group (Table
4). The crude relative risk of pregnancy (levonorgestrel/Yuzpe) was 0.36
(95% confidence intervals: 0.18--0.70). The Breslow-Day test of
homogeneity across centers provided no evidence of a difference in
ratios between centers. Since the upper one-sided 95% confidence bound
levonorgestrel/Yuzpe was 0.70, which is less than 1, the levonorgestrel
regimen was deemed to be more effective than the standard Yuzpe regimen.

[]{#__RefHeading___Toc56513692 .anchor}Table 4: Efficacy Results for
Comparative Clinical Trials from NDA 21‑045 (WHO #92908, WHO 1998b, Ho
1993)

+-----------------------------------+----------------+----------------+
|                                   | **WHO #92908** | **Ho et al.**  |
|                                   |                |                |
|                                   | **(WHO         | **(1993)**     |
|                                   | 1998b)**       |                |
+-----------------------------------+----------------+----------------+
| **Levonorgestrel Group**          |                |                |
+-----------------------------------+----------------+----------------+
| Number of women                   | 976            | 410            |
+-----------------------------------+----------------+----------------+
| Number of pregnancies             | 11             | 12             |
+-----------------------------------+----------------+----------------+
| Pregnancy rate in %               | 1.1            | 2.9            |
+-----------------------------------+----------------+----------------+
| Number of observed/expected       | 11/76.3        | 8/19.8\*       |
| pregnancies^§^                    |                |                |
+-----------------------------------+----------------+----------------+
| Prevented fraction in %           | 86             | 60             |
+-----------------------------------+----------------+----------------+
| **Yuzpe Group**                   |                |                |
+-----------------------------------+----------------+----------------+
| Number of women                   | 979            | 424            |
+-----------------------------------+----------------+----------------+
| Number of pregnancies             | 31             | 15             |
+-----------------------------------+----------------+----------------+
| Pregnancy rate in %, (95% CI)\*\* | 3.2 (2.2, 4.5) | 3.5            |
+-----------------------------------+----------------+----------------+
| Number of observed/expected       | 31/74.2        | 9/22.0\*       |
| pregnancies^§^                    |                |                |
+-----------------------------------+----------------+----------------+
| Prevented fraction in %, (95%     | 58 (41, 72)    | 59\*           |
| CI)\*\*                           |                |                |
+-----------------------------------+----------------+----------------+
| **Comparison of Levonorgestrel to |                |                |
| Yuzpe**                           |                |                |
+-----------------------------------+----------------+----------------+
| Relative risk                     | 0.36           | \--            |
| levonorgestrel/Yuzpe, (95%        | (0.18--0.70)   |                |
| CI)\*\*                           |                |                |
+-----------------------------------+----------------+----------------+

> *^§^ Expected pregnancies calculated using Dixon's expected
> probabilities of pregnancy by cycle day.*
>
> *\* Among 331 women (levonorgestrel group) and 341 women (Yuzpe group)
> who had reliable menstrual dates.*
>
> *\*\* Abbreviation used in this table: CI=Confidence Interval*

Significantly higher pregnancy rates were noted among women who delayed
taking the treatment for two or three days after intercourse when the
results from both the levonorgestrel and Yuzpe arms were combined
(Piaggio 1999). This finding is biologically plausible: the longer the
treatment is delayed, the more likely it is that the woman would have
become pregnant at which time treatment is ineffective. These studies
provide evidence of the high efficacy of Plan B, taken according to the
currently approved labeling.

[]{#__RefHeading___Toc56513641 .anchor}3.2 Controlled Studies of the
Plan B Levonorgestrel Regimen for Emergency Contraception Since the
Submission of NDA 21-045

Three other studies of the Plan B levonorgestrel regimen for emergency
contraception have been completed since the submission of NDA 21-045 and
a fourth study is undergoing final analysis:

1.  The Wu *et al.* (1999) study comparing the efficacy of two doses of
    0.75 mg levonorgestrel with one 10 mg dose of mifepristone in 1,276
    women

2.  The Arowojolu *et al.* (2002) study comparing the efficacy of two
    0.75 mg doses with a single dose of 1.5 mg in 1,118 women at two
    sites in Nigeria

3.  The WHO (2002) multi-center study comparing the efficacy of two 0.75
    mg doses with a single dose of 1.5 mg and a single dose of 10 mg
    mifepristone in 4,071 women at 15 sites in 10 countries

Two of the three studies, Arowojolu *et al.* (2002) and the multi-center
international study conducted by WHO (2002) were designed, in part, to
test alternate dosing regimens. The new studies completed since the
submission of NDA 21-045 support the high efficacy of levonorgestrel for
emergency contraception.

[]{#__RefHeading___Toc56513642 .anchor}4 Studies Supporting the OTC
Distribution of Plan B

[]{#__RefHeading___Toc56513643 .anchor}4.1 Overview

Plan B was approved by the FDA for marketing as a prescription product
on 28 July 1999. The proposed change in this supplement to the NDA is a
prescription (Rx) to OTC switch for the use of Plan B as emergency
contraception. The dosage and instructions for use will remain the same,
although the package and package insert have been modified to suit an
OTC environment.

The two OTC studies sponsored by WCC \-- the Plan B OTC Label
Comprehension Study and the Plan B OTC Actual Use Study (Table 5) \--
were designed, coordinated and monitored by Family Health International
(FHI). These studies were designed to evaluate whether Plan B can be
used safely and effectively without oversight by a licensed medical
practitioner. The Label Comprehension Study was conducted first to
evaluate an OTC label prototype and women's ability to understand the
instructions for use (WCC/FHI 2001). The study was recently published
(Raymond 2002a). The ensuing modified label prototype was used for the
Actual Use Study.

[]{#__RefHeading___Toc56513693 .anchor}Table 5: Sponsor Studies
Supporting OTC Distribution of Plan B

+-----------------+-------------------------------+----------+-------+
| **Study**       | **Rationale**                 | **Number | **    |
|                 |                               | of       | Desig |
|                 |                               | Su       | n\*** |
|                 |                               | bjects** |       |
|                 |                               |          |       |
|                 |                               | **Rec    |       |
|                 |                               | ruited** |       |
+-----------------+-------------------------------+----------+-------+
| **Plan B OTC    | This study was designed to    | 663      | MC,   |
| Label           | evaluate comprehension of the |          | OL    |
| Comprehension   | prototype OTC package label   | (656 in  |       |
| Study**         | for Plan B.                   | a        |       |
|                 |                               | nalysis) |       |
| (WCC/FHI 2001;  |                               |          |       |
| Raymond 2002a)  |                               |          |       |
+-----------------+-------------------------------+----------+-------+
| **Plan B OTC    | This study was designed to    | 665      | MC,   |
| Actual Use      | provide information on the    |          | OL    |
| Study**         | ability of the target         | [        |       |
|                 | population to self-select and | ]{.mark} |       |
| (WCC/FHI 2002)  | appropriately use Plan B when |          |       |
|                 | labeled for OTC use. The      | (540 in  |       |
|                 | primary objective was to      | efficacy |       |
|                 | estimate the frequency of     | a        |       |
|                 | contraindicated and incorrect | nalysis) |       |
|                 | uses of Plan B when dispensed |          |       |
|                 | under simulated OTC           |          |       |
|                 | conditions. Secondary         |          |       |
|                 | objectives were to estimate   |          |       |
|                 | the incidence of repeat use,  |          |       |
|                 | pregnancy and adverse events. |          |       |
+-----------------+-------------------------------+----------+-------+

*\* Abbreviations used in this table: MC=Multi-Center, OL = Open Label,
OTC = Over-The-Counter*

As agreed upon at the meeting held on 5 February 2001 with the FDA
Division of Reproductive and Urologic Drug Products (DRUDP), the
Division of Over-the-Counter Drug Products and representatives of WCC,
the Plan B OTC Actual Use Study was considered the pivotal study and its
results are the primary source of data to support the Rx-to-OTC switch.
When used according to instructions, the approved dosage and regimen
have been judged safe and effective by the FDA. Therefore, the Actual
Use Study was designed primarily to show that women could use the
product appropriately and according to directions, without counseling or
medical oversight. (A discussion of the study design can be found in
Section 4.3.1 below).

The proposed OTC product labeling was developed according to current FDA
content and formatting requirements (21 CFR 201.60--201.66) and was
written to be understood by women of low literacy. Important efficacy
information from the prescription product labeling is addressed in the
proposed OTC labeling.

The OTC label used in the Label Comprehension Study was revised based on
the results of that study, and the revised label was then used in the
Actual Use Study (see Appendix 4). The Actual Use Study OTC label was
then submitted as part of\
the sNDA.

On 15 October 2003, WCC submitted an amendment to the R~x~-to-OTC sNDA
application in response to an oral request from FDA made on 26 September
2003. At that time, FDA requested a copy of the OTC prototype labeling
from the Label Comprehension Study, the Actual Use Study, and the
proposed commercial labeling. These labels appear in Appendices 3, 4,
and 5, respectively.

Changes between the Actual Use Study prototype and the proposed OTC
commercial labeling were:

-   The percentages listed for the incidence of side effects were
    removed, consistent with other OTC labeling.

-   The statement on unusual vaginal bleeding appeared in the Warning
    section of the Plan B package for the Label Comprehension and Actual
    Use studies and in the proposed OTC product package. A second
    statement concerning unusual vaginal bleeding was moved from the
    contraindications to the side effect section of the proposed OTC
    product package.

The package proposed in the sNDA is a 3¼″ × 3″ package (see Appendix 5).
Although the changes described above were made to the proposed OTC
package, the size of the package studied was identical in both the Label
Comprehension and Actual Use studies to that proposed for marketing in
the sNDA.

The sponsor is now proposing to insert this 3¼″ × 3″ package into a
larger outer package. The larger outer package will have identical
labeling to the smaller inner package but in a larger and thus more
legible font. A package insert will also be included in the larger
package. Additional consumer-tested information will also be enclosed in
the larger package. Information on Plan B, its appropriate use, sexually
transmitted diseases, and routine forms of birth control are proposed
for inclusion. Rough drafts of some of this additional information (not
yet studied in the target population) appear in Appendix 7. In addition,
a card designed for the patient to record the time of the first dose and
the projected time of the second dose will be provided.

[]{#__RefHeading___Toc56513644 .anchor}4.2 Plan B OTC Label
Comprehension Study

[]{#__RefHeading___Toc56513645 .anchor}4.2.1 Overview and Study Design

Prototype labeling for the Plan B OTC product was evaluated in the Label
Comprehension Study (WCC/FHI 2001). The study took place in malls and
family planning clinics in eight geographically representative U.S.
cities between 18 June and 12 July 2001. Every effort was made --
including the use of enrollment quotas based on demographics -- to
enroll a target population that was highly diverse and adequate for
subgroup analyses among all groups in the general population likely to
be represented in the OTC population of Plan B users. The focus of this
study was to determine the proportion of subjects who demonstrated
"understanding" of eleven prospectively defined communication objectives
developed with the FDA that were thought to be important for safe and
effective use of Plan B. These objectives addressed indications for use,
contraindications, instructions, possible side effects, and management
of serious complications of use. All eleven communication objectives
were defined prior to study initiation. The results of the study were
published (Raymond 2002a).

The eleven communication objectives were developed by consensus of WCC,
FHI, and consultants. The FDA had many comments and suggestions,
particularly on the individual questions; most were incorporated.
Results of informal and formal pretests of the questionnaire were also
considered in the finalization of the questions.

The table that follows summarizes the definition used to define each
communication objective.

+----------------------------------+-----------------------------------+
| **Communication Objective**      | **Responses that operationally    |
|                                  | define comprehension of the       |
|                                  | objective**                       |
+----------------------------------+-----------------------------------+
| 1.  Plan B^®^ is indicated for   | at least two of the following: 7, |
|     prevention of pregnancy      | 14, 16, 19                        |
|     after unprotected sex.       |                                   |
+----------------------------------+-----------------------------------+
| 2.  Plan B^®^ is intended as a   | at least three of the following:  |
|     back up method and should    | 9, 21, 22, 25                     |
|     not be used for regular      |                                   |
|     contraception.               |                                   |
+----------------------------------+-----------------------------------+
| 3.  Plan B^®^ does not prevent   | 13 and 27                         |
|     sexually transmitted         |                                   |
|     diseases or HIV/AIDS.        |                                   |
+----------------------------------+-----------------------------------+
| 4.  The first pill should be     | at least two of the following: 10 |
|     taken within 72 hours after  | (if response mentions 72 hours or |
|     intercourse.                 | 3 days), 29, (19 and 20)          |
+----------------------------------+-----------------------------------+
| 5.  The first pill should be     | 10 (if response mentions as soon  |
|     taken as soon as possible    | as possible) or 26                |
|     after intercourse.           |                                   |
+----------------------------------+-----------------------------------+
| 6.  The second pill should be    | 30                                |
|     taken 12 hours after the     |                                   |
|     first.                       |                                   |
+----------------------------------+-----------------------------------+
| 7.  Plan B^®^ should not be used | 11 or 17                          |
|     by women who are already     |                                   |
|     pregnant (because it will    |                                   |
|     not be effective).           |                                   |
+----------------------------------+-----------------------------------+
| 8.  Plan B^®^ should not be used | 15                                |
|     by women with unexplained    |                                   |
|     vaginal bleeding             |                                   |
+----------------------------------+-----------------------------------+
| 9.  Plan B^®^ should not be used | 18                                |
|     by women with allergy to any |                                   |
|     ingredient in the product.   |                                   |
+----------------------------------+-----------------------------------+
| 10. Side effects of Plan B^®^    | (32 and 34) or nausea/vomiting    |
|     include nausea and vomiting. | mentioned in answer to 37, unless |
|                                  | she answered \"yes\" to all of    |
|                                  | 32-36                             |
+----------------------------------+-----------------------------------+
| 11. If severe abdominal pain     | 31                                |
|     develops, the user should    |                                   |
|     seek medical care            |                                   |
|     immediately.                 |                                   |
+----------------------------------+-----------------------------------+

A total of 663 interviews were conducted in the Label Comprehension
Study. To be eligible, subjects had to self-report that they were able
to read English well enough to read an OTC product label. They also
could not have a marketing or healthcare background or have previously
participated in this study. Of those interviewed, 656 women between the
ages of 12 and 50 met the inclusion criteria and were included in the
analysis. Of the seven women not considered eligible, 3 were more than
50 years old, 2 did not read English, one had a healthcare/marketing
background, and one provided missing data for all of the five questions
regarding eligibility. This resulting number of eligible subjects
exceeded the target sample size of 575. The target sample size was
established to make possible the determination of the proportion of
women who understood each communication objective with a 95% confidence
interval (conservatively assuming that the proportion would be 50%). The
target also reflected advice from the FDA on the usefulness of subgroup
analyses. Most subjects (582; 89% of the total eligible subjects) were
enrolled at malls. The other 73 (11%) were enrolled at clinics. Clinics
were included because the ethics board of FHI required that minors
enrolled at malls have parental consent to participate in the study.
This requirement was waived at clinics because minors can receive
clinical services in that setting without parental consent.

[]{#__RefHeading___Toc56513646 .anchor}4.2.2 Survey Overview

A standardized questionnaire was used to precisely guide conduct of the
survey for each subject (see Appendix 2). As described in detail below,
a series of standardized questions were asked in a specific order after
the subject had the opportunity to inspect or refer to various portions
of the prototype OTC Plan B package\
(see Appendix 2). Answers to all open-ended questions were recorded
verbatim and subsequently categorized (e.g., see Appendix 6). Correct
answers were prospectively defined. At the suggestion of the FDA,
"acceptable" answers to some questions were also defined (see Appendix
2). Verbatim responses were categorized as acceptable before tabulation
of results.

[]{#__RefHeading___Toc56513647 .anchor}4.2.3 Survey Procedure

For the survey, each subject was given a prototype OTC Plan B package
(see Appendix 3). Each woman was instructed first to look at the outside
of the package (i.e., Appendix 3, Panels 1 and 13) as if she were
thinking about whether to purchase the product in a pharmacy. The
subject was instructed to "take as much or as little time as you
normally would in a drugstore." The package was retrieved, and the
interviewer asked the subject to respond from memory to the following
question "Without looking at the label, tell me what Plan B is used
for?" (Question 7, see Appendix 2).

The package was then returned to the subject, and she was permitted to
inspect the outside (i.e., Appendix 3, Panels 1 and 13), while the
interviewer asked Questions 8-12 (see Appendix 2).

The subject was then told to open the package and review it as if she
were about to use the product at home. She was permitted to refer to the
entire label while the reviewer asked Questions 13-37 (see Appendix 2).
The questions were both multiple choice and open‑ended. After completing
the product questionnaire, the interviewer recorded demographic
information about the subject. Finally, the subject was asked to
complete a self-administered questionnaire about her sexual and
contraceptive history.

[]{#__RefHeading___Toc56513648 .anchor}4.2.4 Study Population

The socio-demographic characteristics of the 656 subjects who were
analyzed in the Label Comprehension Study are summarized in Table 6.
Statistics are presented alongside the comparable distribution of women
in the U.S. population. Enrollment quotas were set to ensure that the
study population included representative numbers of women with
characteristics of particular interest (e.g., 17-25 years old). These
quotas were based on a review of census data on the demographic
characteristics of U.S. women of reproductive age and the desire to
include sufficient women for subgroup analyses.

[]{#_Ref56425572 .anchor}

Table 6: Socio-Demographic Characteristics of the Eligible Population in
the Plan B OTC Label Comprehension Study

  ---------------------------------------- --------------- ---------------
  **Demographic Breakdown**                **Label         **U.S. Women
                                           Comprehension   (Age
                                           Study Number of 12-50)^\*^**
                                           Women (%)**     

  ***Age (years)***                                        

  12-16                                    76 (11.6)       12.3%

  17-25                                    355 (54.1)      21.4%

  26-50                                    225 (34.3)      66.3%

  ***Race***                                               

  Asian or Pacific Islander                30 (4.6)        4.4%

  American Indian or Alaska Native         6 (0.9)         1.0%

  Black                                    155 (23.6)      13.5%

  White                                    324 (49.4)      72.8%

  Other                                    115 (17.5)      

  Refused/Missing                          26 (4.0)        

  ***Marital Status***                                     

  Single                                   487 (74.2)      

  Married                                  143 (21.8)      

  Divorced                                 17 (2.6)        

  Widowed                                  8 (1.2)         

  Refused/Missing                          1 (0.2)         

  ***Ethnicity***                                          

  Hispanic                                 154 (23.5)      13.1%

  Not Hispanic                             500 (76.2)      86.9%

  Refused/Missing                          2 (0.3)         

  ***Highest Level of Education\*\****                     

  6^th^ Grade or less                      4 (0.6)         2%

  7^th^ - 8^th^ Grade                      26 (4.0)        3%

  9^th^ - 12^th^ Grade (not completed high 148 (22.6)      14%
  school)                                                  

  Completed high school or GED             199 (30.3)      28%

  Vocation/Techical school                 18 (2.7)        ND

  Less than 4 years of college             117 (17.8)      29%

  Completed college                        105 (16.0)      17%

  Graduate school                          37 (5.6)        2%

  Refused/Missing                          2 (0.3)         ND
  ---------------------------------------- --------------- ---------------

> *\* Data is from the U.S. Census 2000.*
>
> *\*\* Data from U.S. population include women age 15-54*
>
> *ND = Not Done*

Almost 12% of participants were between the ages of 12 and 16 years, a
figure comparable to their proportion in the U.S. population of women,
aged 12--50. Consistent with the aims of the Label Comprehension Study
to enroll a sample of subjects most consistent with the primary target
population expected to use Plan B, the proportion of women in the study
age 17-25 was more than twice the proportion in that age group who make
up the U.S. population. Black and Hispanic women were also
over-represented relative to the general American population in an
effort to ensure a study sample that reflected a heterogeneous
cross-section of ethnicity. The study also included overall a higher
proportion of women with lower education than the general population.

Subjects were seen at four clinics (N=73 subjects) and eight shopping
malls (N=583 subjects). Table 7 summarizes the distribution of subjects
by age group who were seen in mall and clinic settings:

[]{#__RefHeading___Toc56513695 .anchor}Table 7: Distribution of Eligible
Subjects Seen at Mall and Clinic Settings, by Age Group

  ----------------- ----------- ---------------- ------------- -----------
                    **Age Group                                
                    (in                                        
                    Years)**                                   

  **Study Setting** **12-13**   **14-16**        **17-25**     **26-50**

  **Mall (N=583)**  2.7%        9.4%             51.3%         36.5%

  **Clinic (N=73)** 1.4%        5.5%             76.7%         16.4%
  ----------------- ----------- ---------------- ------------- -----------

As expected, subjects 17-25 years of age were represented to a larger
proportion (76.7%) at clinics than at malls (51.3%). This was almost
certainly a result of the fact that women coming to clinics tended, in
general, to be in 17-25 year old age group, as many of the clinics were
situated near college campuses and this is the age group that clinics
tend to draw from. Note that the percentages associated with each
distribution in the table above should be viewed with some caution, as
the number of subjects seen at clinics is just 11% of the total number
of eligible subjects seen in the Label Comprehension Study.

Study participants were likely users of an OTC product for emergency
contraception given their sexual and contraceptive history (Table 8).
More than three-quarters (79%) of the women who responded to the sexual
history questionnaire were sexually experienced; and, of these, most
(71%) had experienced unprotected intercourse despite a desire not to
become pregnant. More than two-thirds had worried about an unintended
pregnancy at some time in the past (70%). More than half of subjects who
had used oral contraceptive pills reported having missed taking pills
and 40% of those who had used condoms had experienced a condom break.
However, only 32 (6%) of the sexually experienced subjects had ever
previously used emergency contraceptive pills.

[]{#__RefHeading___Toc56513696 .anchor}Table 8: Contraceptive History of
the Eligible Population in the Plan B OTC Label Comprehension Study

  ------------------------------------------- ---------------------------
  ***Sexual and Contraceptive History***      ***Number (%)\* Who
                                              Responded***

  *Ever had sex*                              *474 (79)*

  Had sex in past 3 months                    383 (82)

  Ever used ECPs                              32 (6)

  Ever used condom                            410 (89)

  Ever had condom break (of those who ever    155 (40)
  used a condom)                              

  Ever used oral contraceptive pills          284 (61)

  Ever missed oral contraceptive pill (of     159 (57)
  those who ever used oral contraceptive      
  pills)                                      

  Ever used spermicide                        89 (18)

  Ever used injectable                        83 (17)

  Ever used withdrawal                        204 (43)

  Ever used rhythm                            40 (8)

  Ever used other method                      54 (11)

  Ever had unprotected sex but did not want   314 (71)
  pregnancy                                   

  Ever worried about unwanted pregnancy       315 (70)

  Any pregnancy scare (condom break, missed   390 (82)
  pills, unprotected sex, worry about         
  unwanted pregnancy)                         
  ------------------------------------------- ---------------------------

> *\* Percentages here are expressed as % of those who responded. The
> number of respondents varies by question with those providing
> conflicting responses or missing responses excluded.*

In summary, demographic results suggest that the target population for
the Label Comprehension Study was well represented and consistent with
the study's aim to enroll a representative, diverse group of subjects
that would 1) include a significant contingent of the target population
most likely to use Plan B, 2) include a representative group of subjects
considered at greatest risk of failure to understand the labeled
instructions for product use, and 3) not be biased by the inclusion of
subjects with educational levels too high to obtain a fair assessment of
label comprehension using proposed OTC label language.

[]{#__RefHeading___Toc56513649 .anchor}4.2.5 Results -- All Patients

[]{#__RefHeading___Toc56513650 .anchor}4.2.5.1 Communication Objectives

Results for the 11 prospectively defined communication objectives were
tabulated based on assessment of the survey questions comprising the
definition of each objective.

Table 9 summarizes the results associated with the percentage of correct
responses obtained for each communication objectives. In addition to
presenting results for the entire 656 eligible subject sample, summary
data have also been stratified by age grouping (12-16, 17-25, 26-50
years old), and setting (mall, clinic).

[]{#__RefHeading___Toc56513697 .anchor}Table 9: Percent of Subjects Who
Understood Communication Objectives Related to Efficacy in the Plan B
OTC Label Comprehension Study

+------------------------------+-----+-----+-----+-----+-----+-------+
| **Objective**                | **  |     |     | **  |     | **T   |
|                              | Age |     |     | Set |     | otal\ |
|                              | G   |     |     | tin |     | (N=6  |
|                              | rou |     |     | g** |     | 56)** |
|                              | p** |     |     |     |     |       |
+==============================+=====+=====+=====+=====+=====+=======+
|                              | **  | **  | **  | *   | **C |       |
|                              | 12- | 17- | 26- | *Ma | lin |       |
|                              | 16\ | 25\ | 50\ | ll\ | ic\ |       |
|                              | (n  | (n= | (n= | (n= | (n  |       |
|                              | =76 | 355 | 225 | 583 | =73 |       |
|                              | )** | )** | )** | )** | )** |       |
+------------------------------+-----+-----+-----+-----+-----+-------+
| > 1 Plan B is indicated for  | 8   | 9   | 9   | 9   | 9   | 93.4  |
| > prevention of pregnancy    | 6.8 | 3.5 | 5.6 | 3.5 | 3.2 |       |
| > after unprotected sex.\*   |     |     |     |     |     |       |
+------------------------------+-----+-----+-----+-----+-----+-------+
| > 2 Plan B is intended as a  | 5   | 6   | 7   | 6   | 6   | 67.8  |
| > back up method and should  | 7.9 | 7.6 | 1.6 | 8.6 | 1.6 |       |
| > not be used for regular    |     |     |     |     |     |       |
| > contraception.             |     |     |     |     |     |       |
+------------------------------+-----+-----+-----+-----+-----+-------+
| > 3 Plan B does not prevent  | 9   | 9   | 9   | 9   | 9   | 94.7  |
| > sexually transmitted       | 3.4 | 6.6 | 2.0 | 4.3 | 7.3 |       |
| > diseases or HIV/ AIDS.     |     |     |     |     |     |       |
+------------------------------+-----+-----+-----+-----+-----+-------+
| > 4 The first pill should be | 7   | 8   | 8   | 8   | 8   | 85.7  |
| > taken within 72 hours      | 7.6 | 6.5 | 7.1 | 5.4 | 7.7 |       |
| > after intercourse.         |     |     |     |     |     |       |
+------------------------------+-----+-----+-----+-----+-----+-------+
| > 5 The first pill should be | 8   | 8   | 8   | 8   | 7   | 82.9  |
| > taken as soon as possible  | 4.2 | 3.7 | 1.3 | 3.4 | 9.5 |       |
| > after intercourse.         |     |     |     |     |     |       |
+------------------------------+-----+-----+-----+-----+-----+-------+
| > 6 The second pill should   | 7   | 9   | 8   | 8   | 9   | 85.8  |
| > be taken 12 hours after    | 7.6 | 0.1 | 1.8 | 5.2 | 0.4 |       |
| > the first.\*\*             |     |     |     |     |     |       |
+------------------------------+-----+-----+-----+-----+-----+-------+
| > **7** Plan B should not be | 9   | 9   | 9   | 9   | 9   | 98.6  |
| > used by women who are      | 7.4 | 9.4 | 7.8 | 8.6 | 8.6 |       |
| > already pregnant.          |     |     |     |     |     |       |
+------------------------------+-----+-----+-----+-----+-----+-------+
| > 8 Plan B should not be     | 7   | 7   | 7   | 7   | 7   | 75.8  |
| > used by women with         | 2.4 | 7.2 | 4.7 | 5.6 | 6.7 |       |
| > unexplained vaginal        |     |     |     |     |     |       |
| > bleeding.                  |     |     |     |     |     |       |
+------------------------------+-----+-----+-----+-----+-----+-------+
| > 9 Plan B should not be     | 9   | 9   | 9   | 9   | 9   | 91.3  |
| > used by women with allergy | 0.8 | 1.5 | 1.1 | 1.1 | 3.2 |       |
| > to any ingredient in the   |     |     |     |     |     |       |
| > product.                   |     |     |     |     |     |       |
+------------------------------+-----+-----+-----+-----+-----+-------+
| 10 Side effects of Plan B    | 9   | 9   | 8   | 8   | 9   | 89.6  |
| include nausea and vomiting. | 0.8 | 3.0 | 4.0 | 8.5 | 8.6 |       |
+------------------------------+-----+-----+-----+-----+-----+-------+
| 11 If severe abdominal pain  | 8   | 8   | 7   | 8   | 8   | 81.6  |
| develops, the user should    | 1.6 | 4.2 | 7.3 | 1.3 | 3.6 |       |
| seek medical care            |     |     |     |     |     |       |
| immediately.                 |     |     |     |     |     |       |
+------------------------------+-----+-----+-----+-----+-----+-------+

\* Using an acceptable definition for question 7 from the full study
report (WCC/FHI 2001)

\*\* Using an acceptable definition for question 30 from the full study
report (WCC/FHI 2001)

Subjects in the clinic and mall settings provided very similar correct
response rates to the 11 objectives. Thus, setting does not appear to
have influenced the outcome.

Overall, consistent responses for each communication objective were
observed across both age and study setting groupings. For Objectives 2
and 8, the correct response rates were somewhat lower than for the other
nine objectives across all subgroups. Additional analysis of these
findings led to the observation that one or more questions making-up the
objective may have either been ambiguous or otherwise problematic for
the subject to satisfactorily answer. Objective 4 will also be addressed
since the 12-16 age group demonstrated slightly lower correct response
rates than the other subgroups evaluated.

[]{#__RefHeading___Toc56513651 .anchor}4.2.5.2 Communication Objective 2

Communication Objective 2 focused on use of Plan B as a back up method
that should not be used for regular contraception. Correct response to
at least three of the four questions comprising Communication Objective
2 operationally defined correct comprehension of this objective. Low
response percentages for Communication Objective 2 were seen for all
subgroups (see Table 10).

[]{#_Ref56447800 .anchor}

Table 10: Correct Response Percentages for Questions 9, 21, 22, and 25
Making Up Communication Objective 2: Plan B is Intended as a Back Up
Method and Should Not Be Used for Regular Birth Control

+---+------------------------+--------+---------+----------+---------+
| > |                        |        |         |          |         |
|   |                        |        |         |          |         |
| * |                        |        |         |          |         |
| * |                        |        |         |          |         |
| A |                        |        |         |          |         |
| g |                        |        |         |          |         |
| e |                        |        |         |          |         |
| > |                        |        |         |          |         |
|   |                        |        |         |          |         |
| G |                        |        |         |          |         |
| r |                        |        |         |          |         |
| o |                        |        |         |          |         |
| u |                        |        |         |          |         |
| p |                        |        |         |          |         |
| > |                        |        |         |          |         |
|   |                        |        |         |          |         |
| ( |                        |        |         |          |         |
| Y |                        |        |         |          |         |
| r |                        |        |         |          |         |
| s |                        |        |         |          |         |
| ) |                        |        |         |          |         |
| * |                        |        |         |          |         |
| * |                        |        |         |          |         |
+===+========================+========+=========+==========+=========+
| * |                        | **     | *       | **26-50\ | *       |
| * |                        | 12-16\ | *17-25\ | (        | *Total\ |
| Q |                        | (N     | (N      | N=225)** | (N      |
| u |                        | =76)** | =355)** |          | =656)** |
| e |                        |        |         |          |         |
| s |                        |        |         |          |         |
| t |                        |        |         |          |         |
| i |                        |        |         |          |         |
| o |                        |        |         |          |         |
| n |                        |        |         |          |         |
| s |                        |        |         |          |         |
| * |                        |        |         |          |         |
| * |                        |        |         |          |         |
+---+------------------------+--------+---------+----------+---------+
| * |                        | 57.9%  | 67.6%   | 71.6%    | 67.8%   |
| * |                        |        |         |          |         |
| * |                        |        |         |          |         |
| O |                        |        |         |          |         |
| v |                        |        |         |          |         |
| e |                        |        |         |          |         |
| r |                        |        |         |          |         |
| a |                        |        |         |          |         |
| l |                        |        |         |          |         |
| l |                        |        |         |          |         |
| R |                        |        |         |          |         |
| e |                        |        |         |          |         |
| s |                        |        |         |          |         |
| u |                        |        |         |          |         |
| l |                        |        |         |          |         |
| t |                        |        |         |          |         |
| s |                        |        |         |          |         |
| , |                        |        |         |          |         |
| C |                        |        |         |          |         |
| o |                        |        |         |          |         |
| r |                        |        |         |          |         |
| r |                        |        |         |          |         |
| e |                        |        |         |          |         |
| c |                        |        |         |          |         |
| t |                        |        |         |          |         |
| R |                        |        |         |          |         |
| e |                        |        |         |          |         |
| s |                        |        |         |          |         |
| p |                        |        |         |          |         |
| o |                        |        |         |          |         |
| n |                        |        |         |          |         |
| s |                        |        |         |          |         |
| e |                        |        |         |          |         |
| f |                        |        |         |          |         |
| o |                        |        |         |          |         |
| r |                        |        |         |          |         |
| O |                        |        |         |          |         |
| b |                        |        |         |          |         |
| j |                        |        |         |          |         |
| e |                        |        |         |          |         |
| c |                        |        |         |          |         |
| t |                        |        |         |          |         |
| i |                        |        |         |          |         |
| v |                        |        |         |          |         |
| e |                        |        |         |          |         |
| 2 |                        |        |         |          |         |
| : |                        |        |         |          |         |
| * |                        |        |         |          |         |
| * |                        |        |         |          |         |
| ( |                        |        |         |          |         |
| c |                        |        |         |          |         |
| o |                        |        |         |          |         |
| r |                        |        |         |          |         |
| r |                        |        |         |          |         |
| e |                        |        |         |          |         |
| c |                        |        |         |          |         |
| t |                        |        |         |          |         |
| r |                        |        |         |          |         |
| e |                        |        |         |          |         |
| s |                        |        |         |          |         |
| p |                        |        |         |          |         |
| o |                        |        |         |          |         |
| n |                        |        |         |          |         |
| s |                        |        |         |          |         |
| e |                        |        |         |          |         |
| f |                        |        |         |          |         |
| o |                        |        |         |          |         |
| r |                        |        |         |          |         |
| a |                        |        |         |          |         |
| t |                        |        |         |          |         |
| l |                        |        |         |          |         |
| e |                        |        |         |          |         |
| a |                        |        |         |          |         |
| s |                        |        |         |          |         |
| t |                        |        |         |          |         |
| 3 |                        |        |         |          |         |
| o |                        |        |         |          |         |
| f |                        |        |         |          |         |
| t |                        |        |         |          |         |
| h |                        |        |         |          |         |
| e |                        |        |         |          |         |
| q |                        |        |         |          |         |
| u |                        |        |         |          |         |
| e |                        |        |         |          |         |
| s |                        |        |         |          |         |
| t |                        |        |         |          |         |
| i |                        |        |         |          |         |
| o |                        |        |         |          |         |
| n |                        |        |         |          |         |
| s |                        |        |         |          |         |
| ) |                        |        |         |          |         |
| * |                        |        |         |          |         |
+---+------------------------+--------+---------+----------+---------+
| * | According to the       | 77.6%  | 87.0%   | 85.3%    | 85.4%   |
| * | label, should Plan B   |        |         |          |         |
| 9 | be used as regular     |        |         |          |         |
| : | birth control? (NO)    |        |         |          |         |
| * |                        |        |         |          |         |
| * |                        |        |         |          |         |
+---+------------------------+--------+---------+----------+---------+
| * | A woman is planning to | 50.0%  | 49.6%   | 40.9%    | 46.6%   |
| * | have sex tonight. She  |        |         |          |         |
| 2 | usually uses condoms   |        |         |          |         |
| 1 | to prevent pregnancy.  |        |         |          |         |
| : | This time she plans to |        |         |          |         |
| * | use Plan B instead     |        |         |          |         |
| * | because her husband    |        |         |          |         |
|   | complains about using  |        |         |          |         |
|   | condoms. Is this a     |        |         |          |         |
|   | correct use of Plan B  |        |         |          |         |
|   | ? (NO)                 |        |         |          |         |
+---+------------------------+--------+---------+----------+---------+
| * | A woman used Plan B    | 90.8%  | 91.0%   | 89.8%    | 90.5%   |
| * | every day instead of   |        |         |          |         |
| 2 | her usual birth        |        |         |          |         |
| 2 | control pills. Was     |        |         |          |         |
| : | this a correct use of  |        |         |          |         |
| * | Plan B ? (NO)          |        |         |          |         |
| * |                        |        |         |          |         |
+---+------------------------+--------+---------+----------+---------+
| * | A woman and her        | 59.2%  | 65.6%   | 75.6%    | 68.3%   |
| * | husband do not like    |        |         |          |         |
| 2 | using condoms, and the |        |         |          |         |
| 5 | woman does not want to |        |         |          |         |
| : | take birth control     |        |         |          |         |
| * | pills. They decide to  |        |         |          |         |
| * | use Plan B as their    |        |         |          |         |
|   | main contraceptive     |        |         |          |         |
|   | method. Is this a      |        |         |          |         |
|   | correct use of Plan B? |        |         |          |         |
|   | (NO)                   |        |         |          |         |
+---+------------------------+--------+---------+----------+---------+

It is clear from this presentation that questions 21 and 25 presented
more of a challenge to the women surveyed. For the 12-16 year old group,
77.6% were able to correctly answer that Plan B was not a regular birth
control method (Question 9); over 90% of them understood the scenario
described in Question 22 to correctly answer that Plan B was
[not]{.underline} an "every day", "regular" birth control method. It
could be speculated that the two younger age groups, particularly the
youngest one, had an easier understanding of the proper use of Plan B
when presented with a scenario that they could evaluate, rather than
simply responding to a direct question. In order to strengthen the
message about appropriate use, however, the message that Plan B is not a
substitute for regular contraception now appears in bold print within
the current, proposed OTC label. The sponsor is proposing to include
additional information in the package discussing more effective and
appropriate methods of birth control.

It is also interesting that, for Question 21, the correct response rate
for the 26-50 year old age group (40.9%) is discernibly lower than for
the two younger age groups (50.0% and 49.6%, respectively), and that
this finding appears to be independent of education level. It is
possible that a greater number of older subjects are married or in
long-term relationships and are more practical when it comes to sex.
These subjects may also be having sex less often than their younger
counterparts. As a result, older subjects may have seen Plan B as
effective contraception for a "planned emergency". Although the product
is not indicated for this use, it may shed some light into the
perception that subjects have regarding whether an "emergency" is
literally that or a "prevention" of an emergency (like keeping a fire
extinguisher on hand in the unlikely event of fire).

[]{#__RefHeading___Toc56513652 .anchor}4.2.5.3 Communication Objective 4

Table 11 displays the proportion of all subjects giving the correct
answer to each question related to Communication Objective 4 for all
subject and for each age group indicated.

[]{#__RefHeading___Toc56513699 .anchor}Table 11: Correct Response
Percentages for Questions 10, 19, 20 and 29 Making Up Communication
Objective 4: The First Pill Should Be Taken Within 72 Hours After
Intercourse

+---+------------------------+--------+---------+----------+---------+
| > |                        |        |         |          |         |
|   |                        |        |         |          |         |
| A |                        |        |         |          |         |
| g |                        |        |         |          |         |
| e |                        |        |         |          |         |
| > |                        |        |         |          |         |
|   |                        |        |         |          |         |
| G |                        |        |         |          |         |
| r |                        |        |         |          |         |
| o |                        |        |         |          |         |
| u |                        |        |         |          |         |
| p |                        |        |         |          |         |
| > |                        |        |         |          |         |
|   |                        |        |         |          |         |
| ( |                        |        |         |          |         |
| Y |                        |        |         |          |         |
| r |                        |        |         |          |         |
| s |                        |        |         |          |         |
| ) |                        |        |         |          |         |
+===+========================+========+=========+==========+=========+
| Q |                        | 12-16\ | 17-25\  | 26-50\   | Total\  |
| u |                        | (N=76) | (N=355) | (N=225)  | (N=656) |
| e |                        |        |         |          |         |
| s |                        |        |         |          |         |
| t |                        |        |         |          |         |
| i |                        |        |         |          |         |
| o |                        |        |         |          |         |
| n |                        |        |         |          |         |
+---+------------------------+--------+---------+----------+---------+
| * |                        | 77.6%  | 86.5%   | 87.1%    | 85.7%   |
| * |                        |        |         |          |         |
| * |                        |        |         |          |         |
| O |                        |        |         |          |         |
| v |                        |        |         |          |         |
| e |                        |        |         |          |         |
| r |                        |        |         |          |         |
| a |                        |        |         |          |         |
| l |                        |        |         |          |         |
| l |                        |        |         |          |         |
| R |                        |        |         |          |         |
| e |                        |        |         |          |         |
| s |                        |        |         |          |         |
| u |                        |        |         |          |         |
| l |                        |        |         |          |         |
| t |                        |        |         |          |         |
| s |                        |        |         |          |         |
| , |                        |        |         |          |         |
| C |                        |        |         |          |         |
| o |                        |        |         |          |         |
| r |                        |        |         |          |         |
| r |                        |        |         |          |         |
| e |                        |        |         |          |         |
| c |                        |        |         |          |         |
| t |                        |        |         |          |         |
| R |                        |        |         |          |         |
| e |                        |        |         |          |         |
| s |                        |        |         |          |         |
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| n |                        |        |         |          |         |
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| * |                        |        |         |          |         |
| * |                        |        |         |          |         |
| * |                        |        |         |          |         |
|   |                        |        |         |          |         |
| * |                        |        |         |          |         |
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| * |                        |        |         |          |         |
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| 4 |                        |        |         |          |         |
| : |                        |        |         |          |         |
| * |                        |        |         |          |         |
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| o |                        |        |         |          |         |
| w |                        |        |         |          |         |
| i |                        |        |         |          |         |
| n |                        |        |         |          |         |
| g |                        |        |         |          |         |
| : |                        |        |         |          |         |
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| s |                        |        |         |          |         |
| t |                        |        |         |          |         |
| i |                        |        |         |          |         |
| o |                        |        |         |          |         |
| n |                        |        |         |          |         |
| 1 |                        |        |         |          |         |
| 0 |                        |        |         |          |         |
| ( |                        |        |         |          |         |
| 7 |                        |        |         |          |         |
| 2 |                        |        |         |          |         |
| h |                        |        |         |          |         |
| o |                        |        |         |          |         |
| u |                        |        |         |          |         |
| r |                        |        |         |          |         |
| s |                        |        |         |          |         |
| / |                        |        |         |          |         |
| 3 |                        |        |         |          |         |
| d |                        |        |         |          |         |
| a |                        |        |         |          |         |
| y |                        |        |         |          |         |
| s |                        |        |         |          |         |
| ) |                        |        |         |          |         |
| , |                        |        |         |          |         |
| 2 |                        |        |         |          |         |
| 9 |                        |        |         |          |         |
| , |                        |        |         |          |         |
| ( |                        |        |         |          |         |
| 1 |                        |        |         |          |         |
| 9 |                        |        |         |          |         |
| & |                        |        |         |          |         |
| 2 |                        |        |         |          |         |
| 0 |                        |        |         |          |         |
| ) |                        |        |         |          |         |
| ) |                        |        |         |          |         |
| * |                        |        |         |          |         |
+---+------------------------+--------+---------+----------+---------+
| 1 | After unprotected sex, | 38     | 6       | 50.6%^1^ | 5       |
| 0 | when is the best time  | .2%^1^ | 0.0%^1^ |          | 4.3%^1^ |
| : | to take the first      |        |         | 24.4%^2^ |         |
|   | tablet? (ASAP AND      | 13     | 2       |          | 2       |
|   | WITHIN 72 HRS OR 3     | .2%^2^ | 5.1%^2^ | 26.2%^3^ | 3.5%^2^ |
|   | DAYS)                  |        |         |          |         |
|   |                        | 25     | 3       |          | 3       |
|   |                        | .0%^3^ | 4.9%^3^ |          | 0.8%^3^ |
+---+------------------------+--------+---------+----------+---------+
| 1 | A woman had            | 82.9%  | 86.2%   | 88.9%    | 86.7%   |
| 9 | unprotected sex 2 days |        |         |          |         |
| : | ago and then used Plan |        |         |          |         |
|   | B to prevent           |        |         |          |         |
|   | pregnancy. Was this a  |        |         |          |         |
|   | correct use of Plan B? |        |         |          |         |
|   | (YES)                  |        |         |          |         |
+---+------------------------+--------+---------+----------+---------+
| 2 | A woman had            | 94.7%  | 94.6%   | 94.2%    | 94.5%   |
| 0 | unprotected sex a week |        |         |          |         |
| : | ago and then used Plan |        |         |          |         |
|   | B to prevent           |        |         |          |         |
|   | pregnancy. Was this a  |        |         |          |         |
|   | correct use of Plan B? |        |         |          |         |
|   | (NO)                   |        |         |          |         |
+---+------------------------+--------+---------+----------+---------+
| 2 | How many days does the | 85.5%  | 91.8%   | 92.4%    | 91.3%   |
| 9 | label say is the       |        |         |          |         |
| : | longest after sex a    |        |         |          |         |
|   | woman should wait      |        |         |          |         |
|   | before taking the      |        |         |          |         |
|   | first Plan B tablet    |        |         |          |         |
|   | \[hours\]? (3 DAYS OR  |        |         |          |         |
|   | 72 HOURS)              |        |         |          |         |
+---+------------------------+--------+---------+----------+---------+

*^1^ Correct or acceptable (ASAP and within 72hours/3days or
72hours/3days)*

*^2^ Correct (ASAP and within 72hours/3days)*

*^3^ Acceptable (within 72hours/3days)*

Communication Objective 4 focused on proper use of Plan B within 72
hours after unprotected intercourse. It is clear from the correct
response rates that Question 10 had a disproportionately low correct
response rate. Correct responses to this question included only
responses that contained a specific reference to the 72-hour window.
This meant that if a subject responded that the best time to take the
first tablet was "as soon as possible", the response was considered not
to be correct. Given the open-ended nature of this question (this
question was not a multiple-choice question), it is understandable that
a subject could have answered "as soon as possible" and not known that a
specific time window was needed to "correctly" answer the question. The
other questions making-up this objective (19, 20 and 29) all have
response rates well over 80% suggesting that subjects clearly understood
the need to take the first tablet within the 72-hour window. In
conclusion, it appears that the low correct response rate to this
objective is not a result of lack of understanding of the objective by
subjects, but merely a result of the definition used to define a
"correct" response to Question 10.

In response to this finding, in addition to the statement included in
the Drug Facts panel of the Label Comprehension label (Panel 13, see
Appendix 4), the sponsor added a second statement to reinforce the
importance of taking the first tablet of\
Plan B within 72 hours of unprotected sex to Panel 8 of the Actual Use
Study label.

[]{#__RefHeading___Toc56513653 .anchor}4.2.5.4 Communication Objective 8

Table 12 displays the proportion of all subjects giving the correct
answer to Question 15 the sole question for Communication Objective 8
for all subject and for each age group indicated.

[]{#__RefHeading___Toc56513700 .anchor}Table 12: Correct Response
Percentages for Question 15 Making Up Communication Objective 8: Plan B
Should Not Be Used by Women with Unexplained Vaginal Bleeding

+---+----------------------------+---+--------+--------+--------+--------+
| > |                            |   |        |        |        |        |
|   |                            |   |        |        |        |        |
| * |                            |   |        |        |        |        |
| * |                            |   |        |        |        |        |
| A |                            |   |        |        |        |        |
| g |                            |   |        |        |        |        |
| e |                            |   |        |        |        |        |
| > |                            |   |        |        |        |        |
|   |                            |   |        |        |        |        |
| G |                            |   |        |        |        |        |
| r |                            |   |        |        |        |        |
| o |                            |   |        |        |        |        |
| u |                            |   |        |        |        |        |
| p |                            |   |        |        |        |        |
| > |                            |   |        |        |        |        |
|   |                            |   |        |        |        |        |
| ( |                            |   |        |        |        |        |
| Y |                            |   |        |        |        |        |
| r |                            |   |        |        |        |        |
| s |                            |   |        |        |        |        |
| ) |                            |   |        |        |        |        |
| * |                            |   |        |        |        |        |
| * |                            |   |        |        |        |        |
+===+============================+===+========+========+========+========+
| * |                            | * |        | **     | **     | **     |
| * |                            | * |        | 17-25\ | 26-50\ | Total\ |
| Q |                            | 1 |        | (N=    | (N=    | (N=    |
| u |                            | 2 |        | 355)** | 225)** | 656)** |
| e |                            | - |        |        |        |        |
| s |                            | 1 |        |        |        |        |
| t |                            | 6 |        |        |        |        |
| i |                            | \ |        |        |        |        |
| o |                            | ( |        |        |        |        |
| n |                            | N |        |        |        |        |
| * |                            | = |        |        |        |        |
| * |                            | 7 |        |        |        |        |
|   |                            | 6 |        |        |        |        |
|   |                            | ) |        |        |        |        |
|   |                            | * |        |        |        |        |
|   |                            | * |        |        |        |        |
+---+----------------------------+---+--------+--------+--------+--------+
| * | A woman had unusual        |   | 72.4%  | 77.2%  | 74.7%  | 75.8%  |
| * | vaginal bleeding during    |   |        |        |        |        |
| 1 | the past week. She had     |   |        |        |        |        |
| 5 | unprotected sex and then   |   |        |        |        |        |
| : | she took Plan B to prevent |   |        |        |        |        |
| * | pregnancy. Was this a      |   |        |        |        |        |
| * | correct use of Plan B?     |   |        |        |        |        |
|   | **(NO)**                   |   |        |        |        |        |
+---+----------------------------+---+--------+--------+--------+--------+

It is unclear as to why unusual vaginal bleeding is considered a
contraindication to use of Plan B in the current prescription label.
Current oral contraceptive labeling includes undiagnosed abnormal
vaginal bleeding as a contraindication. Clearly, in an OTC setting a
potential user cannot be expected to be able to evaluate whether or not
her unusual vaginal bleeding is undiagnosed or abnormal. Given the
results of the responses to this question, unusual vaginal bleeding does
appear in the warning section as well as the side effect section of the
proposed OTC label. In addition, the additional materials contained in
the proposed package for the OTC use of Plan B will be modified to
clarify this concern.

Some other changes were made to the label prior to initiation of the
Actual Use Study based on the findings for Objectives 6 and 11. For
Objective 6, the slightly lower response rate for the youngest age group
led to putting the message that the second Plan B tablet should be taken
12 hours after the first Plan B tablet into bold face type for the label
used in the Actual Use Study. A similar finding among subjects in the
26-50 year-old age group for Objective 11 led to putting the fact that
ectopic pregnancy is a serious medical issue into bold face type for the
label used in the Actual Use Study.

[]{#__RefHeading___Toc56513654 .anchor}4.2.6 Results by Literacy Level
(as assessed by the REALM test)

[]{#__RefHeading___Toc56513655 .anchor}4.2.6.1 Overview

Literacy was assessed in the subgroup of OTC Label Comprehension Study
participants who were 18 years of age or older and who had not completed
college. The instrument used to evaluate literacy was the REALM test
(Rapid Estimate of Adult Literacy in Medicine, Davis et al. 1993). The
REALM test was comprised of a list of 66 words specified in the Label
Comprehension Study questionnaire. The subject was asked to pronounce
each word for the interviewer. The words chosen encompassed those
related to the conditions of use and side effects that might be
associated with a contraceptive product, with the addition of terms
related to women's health and general medical conditions. The words
chosen for the REALM were also considered to be at the literacy level
for which the OTC label was written. The raw REALM score for each
subject was then categorized as follows:

  -------------------------- --------------------------------------------
  [REALM Raw                 [Grade Range Estimate]{.underline}
  Score]{.underline}         

  0-18                       Third Grade and Below

  19-44                      Fourth to Sixth Grade

  45-60                      Seventh to Eight Grade

  61-66                      Ninth Grade and Above
  -------------------------- --------------------------------------------

Although the REALM score provides some information about the consistency
of a subject's reported level of education and her ability to read, the
developers of the instrument point out that the REALM is an estimate of
literacy and not a grade-equivalent determinant. In addition, its role
in evaluating the Label Comprehension Study is considered somewhat
limited because only a subset of subjects participating in the study
were tested. Thus, survey results for those administered the REALM test
were analyzed separately.

A total of 395 subjects were given the REALM test. Their
socio-demographic characteristics are given in Table 13 in total and as
subgroups for those with REALM scores suggesting a literacy level of
[\<]{.underline} 8^th^ grade (N=139) or \> 8^th^ grade (N=254).

[]{#__RefHeading___Toc56513701 .anchor}Table 13: Socio-Demographic
Characteristics of the Subjects Administered the REALM Test in the Plan
B OTC Label Comprehension Study

+-----------------------------------+-----------+-----------+-----------+
| **Demographic Breakdown**         | **Number  |           |           |
|                                   | of Women  |           |           |
|                                   | (%)**     |           |           |
+-----------------------------------+-----------+-----------+-----------+
|                                   | **[\<]{.u | **\>      | **To      |
|                                   | nderline} | 8^th^     | tal^\*^** |
|                                   | 8^th^     | Grade**   |           |
|                                   | Grade**   |           | **N =     |
|                                   |           | **N =     | 395**     |
|                                   | **N =     | 254**     |           |
|                                   | 139**     |           |           |
+-----------------------------------+-----------+-----------+-----------+
| ***Literacy Level***              |           |           |           |
+-----------------------------------+-----------+-----------+-----------+
| 3^rd^ Grade or less               | 1 (0.7)   |          | 1 (0.3)   |
+-----------------------------------+-----------+-----------+-----------+
| 4^th^ -- 6^th^ Grade              | 17 (12.2) |          | 17 (4.3)  |
+-----------------------------------+-----------+-----------+-----------+
| 7^th^ -- 8^th^ Grade              | 121       |          | 121       |
|                                   | (87.1)    |           | (30.6)    |
+-----------------------------------+-----------+-----------+-----------+
| High school                       |          | 254       | 254       |
|                                   |           | (100.0)   | (64.3)    |
+-----------------------------------+-----------+-----------+-----------+
| Missing                           |          |          | 2 (0.5)   |
+-----------------------------------+-----------+-----------+-----------+
| ***Setting***                     |           |           |           |
+-----------------------------------+-----------+-----------+-----------+
| Mall                              | 123       | 219       | 344       |
|                                   | (88.5)    | (86.2)    | (87.1)    |
+-----------------------------------+-----------+-----------+-----------+
| Clinic                            | 16 (11.5) | 35 (13.8) | 51 (12.9) |
+-----------------------------------+-----------+-----------+-----------+
| ***Age (years)***                 |           |           |           |
+-----------------------------------+-----------+-----------+-----------+
| 17-25                             | 92 (66.2) | 182       | 275       |
|                                   |           | (71.7)    | (69.6)    |
+-----------------------------------+-----------+-----------+-----------+
| 26-50                             | 47 (33.8) | 72 (28.3) | 120       |
|                                   |           |           | (30.4)    |
+-----------------------------------+-----------+-----------+-----------+
| ***Race***                        |           |           |           |
+-----------------------------------+-----------+-----------+-----------+
| Asian or Pacific Islander         | 4 (2.9)   | 11 (4.3)  | 15 (3.8)  |
+-----------------------------------+-----------+-----------+-----------+
| American Indian or Alaska Native  | 1 (0.7)   | 1 (0.4)   | 2 (0.5)   |
+-----------------------------------+-----------+-----------+-----------+
| Black                             | 48 (34.5) | 59 (23.2) | 108       |
|                                   |           |           | (27.3)    |
+-----------------------------------+-----------+-----------+-----------+
| White                             | 46 (33.1) | 125       | 172       |
|                                   |           | (49.2)    | (43.5)    |
+-----------------------------------+-----------+-----------+-----------+
| Other                             | 34 (24.5) | 48 (18.9) | 82 (20.8) |
+-----------------------------------+-----------+-----------+-----------+
| Refused/Missing                   | 6 (4.3)   | 10 (3.9)  | 16 (4.1)  |
+-----------------------------------+-----------+-----------+-----------+
| ***Ethnicity***                   |           |           |           |
+-----------------------------------+-----------+-----------+-----------+
| Hispanic                          | 46 (33.1) | 61 (24.0) | 107       |
|                                   |           |           | (27.1)    |
+-----------------------------------+-----------+-----------+-----------+
| Not Hispanic                      | 93 (66.9) | 193       | 288       |
|                                   |           | (76.0)    | (72.9)    |
+-----------------------------------+-----------+-----------+-----------+
| Refused/Missing                   | 8 (5.8)   | 8 (3.1)   | 16 (4.1)  |
+-----------------------------------+-----------+-----------+-----------+
| ***Marital Status***              |           |           |           |
+-----------------------------------+-----------+-----------+-----------+
| Single                            | 106       | 194       | 301       |
|                                   | (76.3)    | (76.4)    | (76.2)    |
+-----------------------------------+-----------+-----------+-----------+
| Married                           | 25 (18.0) | 51 (20.1) | 76 (19.2) |
+-----------------------------------+-----------+-----------+-----------+
| Divorced                          | 4 (2.9)   | 6 (2.4)   | 10 (2.5)  |
+-----------------------------------+-----------+-----------+-----------+
| Widowed                           | 3 (2.2)   | 3 (1.2)   | 7 (1.8)   |
+-----------------------------------+-----------+-----------+-----------+
| Refused/Missing                   | 1 (0.7)   | 0         | 1 (0.3)   |
+-----------------------------------+-----------+-----------+-----------+
| ***Highest Level of Education     |           |           |           |
| Completed***                      |           |           |           |
+-----------------------------------+-----------+-----------+-----------+
| 6^th^ Grade or less               | 0         | 0         | 0         |
+-----------------------------------+-----------+-----------+-----------+
| 7^th^ - 8^th^ Grade               | 3 (2.2)   | 0         | 3 (0.8)   |
+-----------------------------------+-----------+-----------+-----------+
| 9^th^ - 12^th^ Grade (not         | 35 (25.2) | 36 (14.2) | 73 (18.5) |
| completed high school)            |           |           |           |
+-----------------------------------+-----------+-----------+-----------+
| Completed high school or GED      | 66 (47.5) | 120       | 186       |
|                                   |           | (47.2)    | (47.1)    |
+-----------------------------------+-----------+-----------+-----------+
| Vocation/Techical school          | 8 (5.8)   | 10 (3.9)  | 18 (4.6)  |
+-----------------------------------+-----------+-----------+-----------+
| Less than 4 years of college      | 27 (19.4) | 88 (34.6) | 115       |
|                                   |           |           | (29.1)    |
+-----------------------------------+-----------+-----------+-----------+

*\* Total includes 2 subjects who were missing REALM results.*

[]{#__RefHeading___Toc56513656 .anchor}4.2.6.2 Results - Communication
Objectives

Table 14 summarizes the results associated with the percentage of
correct responses obtained for the 11 prospectively defined
communication objectives for those patients who took the REALM test. In
addition to presenting results for the entire 395 subject sample who
participated in the REALM test, summary data have also been included for
the overall 12-16 age group as well as those subjects who completed
college or graduate school.

[]{#__RefHeading___Toc56513702 .anchor}Table 14: Percent of REALM
Subgroup Who Understood Communication Objectives Related to Efficacy in
the Plan B OTC Label Comprehension Study

+-----------------------+-------+--------+---------+-----------+------+
| **Objective**         | **Age | *      | **REALM | **        | **To |
|                       | Gr    | *REALM | Cat     | Completed | tal\ |
|                       | oup** | Cate   | egory** | College   | (    |
|                       |       | gory** |         | or Grad.  | N=65 |
|                       | **    |        | **\>    | School    | 6)** |
|                       | 12-16 | **[\<] | 8^th^   | (N=142)** |      |
|                       | Y     | {.unde | Grade\  |           |      |
|                       | ears\ | rline} | (N      |           |      |
|                       | (N=   | 8^th^  | =254)** |           |      |
|                       | 76)** | Grade\ |         |           |      |
|                       |       | (N=    |         |           |      |
|                       |       | 139)** |         |           |      |
+=======================+=======+========+=========+===========+======+
| 1 Plan B is indicated | 86.8  | 84.2   | 96.9    | 100.0     | 93.4 |
| for prevention of     |       |        |         |           |      |
| pregnancy after       |       |        |         |           |      |
| unprotected sex.      |       |        |         |           |      |
+-----------------------+-------+--------+---------+-----------+------+
| 2 Plan B is intended  | 57.9  | 46.0   | 78.7    | 78.2      | 67.8 |
| as a back up method   |       |        |         |           |      |
| and should not be     |       |        |         |           |      |
| used for regular      |       |        |         |           |      |
| contraception.        |       |        |         |           |      |
+-----------------------+-------+--------+---------+-----------+------+
| 3 Plan B does not     | 93.4  | 84.2   | 99.2    | 97.9      | 94.7 |
| prevent sexually      |       |        |         |           |      |
| transmitted diseases  |       |        |         |           |      |
| or HIV/ AIDS.         |       |        |         |           |      |
+-----------------------+-------+--------+---------+-----------+------+
| 4 The first pill      | 77.6  | 71.9   | 90.2    | 96.5      | 85.7 |
| should be taken       |       |        |         |           |      |
| within 72 hours after |       |        |         |           |      |
| intercourse.          |       |        |         |           |      |
+-----------------------+-------+--------+---------+-----------+------+
| 5 The first pill      | 84.2  | 84.2   | 83.5    | 82.4      | 82.9 |
| should be taken as    |       |        |         |           |      |
| soon as possible      |       |        |         |           |      |
| after intercourse.    |       |        |         |           |      |
+-----------------------+-------+--------+---------+-----------+------+
| 6 The second pill     | 77.6  | 82.0   | 92.5    | 82.4      | 85.8 |
| should be taken 12    |       |        |         |           |      |
| hours after the       |       |        |         |           |      |
| first.                |       |        |         |           |      |
+-----------------------+-------+--------+---------+-----------+------+
| **7** Plan B should   | 97.4  | 95.7   | 99.6    | 100.0     | 98.6 |
| not be used by women  |       |        |         |           |      |
| who are already       |       |        |         |           |      |
| pregnant.             |       |        |         |           |      |
+-----------------------+-------+--------+---------+-----------+------+
| 8 Plan B should not   | 72.4  | 69.1   | 81.9    | 75.4      | 75.8 |
| be used by women with |       |        |         |           |      |
| unexplained vaginal   |       |        |         |           |      |
| bleeding.             |       |        |         |           |      |
+-----------------------+-------+--------+---------+-----------+------+
| 9 Plan B should not   | 90.8  | 82.0   | 95.7    | 94.4      | 91.3 |
| be used by women with |       |        |         |           |      |
| allergy to any        |       |        |         |           |      |
| ingredient in the     |       |        |         |           |      |
| product.              |       |        |         |           |      |
+-----------------------+-------+--------+---------+-----------+------+
| 10 Side effects of    | 90.8  | 84.9   | 96.5    | 82.4      | 89.6 |
| Plan B include nausea |       |        |         |           |      |
| and vomiting.         |       |        |         |           |      |
+-----------------------+-------+--------+---------+-----------+------+
| 11 If severe          | 81.6  | 81.3   | 83.1    | 77.5      | 81.6 |
| abdominal pain        |       |        |         |           |      |
| develops, the user    |       |        |         |           |      |
| should seek medical   |       |        |         |           |      |
| care immediately.     |       |        |         |           |      |
+-----------------------+-------+--------+---------+-----------+------+

Similar to the results seen for all treated patients, satisfactory
response rates were seen for nine of the 11 communication objectives. As
seen in the analysis for all treated subjects, lower correct response
rates were seen for Objectives 2 and 8. In particular, subjects with a
REALM literacy category [\<]{.underline} 8^th^ grade had an appreciably
lower response to Objective 2 than either "high literacy" subjects or
those who completed college or graduate school. In fact, the
[\<]{.underline} 8^th^ grade REALM subgroup had the lowest response
rate. In an effort to insure that as many potential users of Plan B can
adequately comprehend the proper use of Plan B, particularly adults with
a low literacy level, the sponsor has proposed to include additional
information that addresses the fact that Plan B is not intended to be
used as a routine form of birth control. These materials will be tested
in a population with diverse levels of literacy and will consider the
use of graphics and/or pictorials that do not require intense
information processing. However, it is important to note that the
overwhelming majority of all subjects in the Label Comprehension Study
understood and were able to communicate the intent for the use of Plan
B.

For Objective 8, the [\<]{.underline} 8^th^ grade REALM subjects
responded within the same range as both the youngest age group and those
who had completed college or graduate school. Also, as discussed for the
analysis of all treated patients, this objective presented challenges to
all subgroups evaluated and resulted in a revision of the label.

As stated in Section 4.2.4.3, communication objective 4 is
disproportionately impacted by the definition of "correct" response for
Question 10. When this is taken into consideration, the [\<]{.underline}
8^th^ grade literacy subgroup demonstrates an adequate level of
comprehension for this objective.

[]{#__RefHeading___Toc56513657 .anchor}4.2.7 Summary and Conclusions --
Label Comprehension Study

The Plan B OTC Label Comprehension Study was designed to evaluate the
first OTC label prototype for switching Plan B from R~x~ to OTC status.
A diverse, heterogeneous sample of subjects of all races and between the
ages of 12 and 50 years were interviewed. Questions were asked regarding
the proposed OTC product package and the label. Consistent with
conditions that would be commensurate with OTC use, no screening or
counseling by any clinician, pharmacist, or any other healthcare
professional was conducted.

Overall, the 656 subjects studied demonstrated an adequate understanding
of the 11 communication objectives prospectively defined to represent a
satisfactory understanding of the Plan B OTC label used in this study.
However, a lower correct response rate was obtained for Objectives 2, 4
and 8.

The results obtained for Objective 4 may be attributed to the strict
definition used to define the "correct" response to Question 10.
However, the high correct response rate to Question 29 demonstrates that
subjects clearly understood that the longest one should wait before
taking the first Plan B tablet is 3 days or 72 hours after unprotected
sex. Although subjects understood that the first Plan B tablet should be
taken within 72 hours of unprotected sex, an additional statement
concerning the importance of taking the first tablet within 72 hours of
unprotected sex was added to Panel 8 of the label used in the Actual Use
Study (Appendix 4).

The results for Objective 2 suggest that some women were unable to
demonstrate adequate understanding that Plan B is a back-up method only
and should not be used as a routine form of birth control. Although
these results may be attributed to the ambiguity of some of the
questions, given the significance of this objective and the importance
of understanding the need for routine birth control, the sponsor bolded
this statement in the label for the Actual Use Study and in the proposed
Plan B OTC label now being reviewed by the FDA. The sponsor has also
designed an education and outreach program called CARE^SM^ (see Section
6). Specifically with regard to Objective 2, CARE^SM^ proposes inclusion
of information, tested in a low-literacy population, that clearly
communicates the fact that Plan B is not intended to be used as a method
for routine birth control and provides information on alternative birth
control methods.

Responses to Objective 8 also suggest that subjects participating in the
study may not have understood that unusual vaginal bleeding was a
contraindication to use of\
Plan B. It is presumed that the contraindication included in the current
prescription label is an effort to insure that women who are
experiencing undiagnosed abnormal vaginal bleeding (as stated in the
class labeling for oral contraceptives) will seek medical attention.
Although this is important to the patient's long-term well-being, it
does not predispose them to any additional adverse events if Plan B is
used. However, to provide additional support for this communication
objective, an additional statement has been added to Panel 4 in the
proposed Plan B OTC label now being reviewed by the FDA (see Appendix
5).

Although not highlighted above, it is important to note that the
overwhelming majority of subjects demonstrated comprehension of the
communication objective related to STIs and HIV/AIDs (Objective 3). Over
90% of the overall study population answered these questions correctly
-- including the subset of subjects\
aged 12-16.

In conclusion, subjects participating in the study demonstrated
appropriate comprehension of the Plan B OTC label. Several areas were
identified where improvement was thought to be warranted. Modifications
were made to the label in advance of the Actual Use study. Additional
changes to the label and the package

have been proposed in order to maximize the benefits of Plan B for OTC
use.

[]{#__RefHeading___Toc56513658 .anchor}4.3 Plan B OTC Actual Use Study

[]{#__RefHeading___Toc56513659 .anchor}4.3.1 Overview and Study Design

The Plan B OTC Actual Use Study was a non-comparative case series
designed to provide information on whether women seeking emergency
contraception could self-select and use the product appropriately and
safely when it is labeled for OTC distribution. Since efficacy had
already been demonstrated in the controlled trials supporting the NDA
and the dose and regimen are identical to the R~x~ product, the
objective of this study was to estimate the frequency of contraindicated
and incorrect use of Plan B when dispensed under OTC-like conditions
(without medical oversight).

The study took place between November 5, 2001 and April 11, 2002 at five
affiliates of Planned Parenthood Federation of America throughout the
United States as well as five Longs Drugs pharmacies located in the
Seattle, WA area where women were already accustomed to receiving
confidential emergency contraceptive services directly from the
pharmacist. At the time, Washington State was the only state in the
country with a well-established pharmacy access program, so it was not
possible to select a more diverse sample of pharmacy sites. The choice
of sites with well-established emergency contraception services was
justified by the confidential nature of the product and by the current
low level of awareness of emergency contraception in the general public.
It would not have been feasible to conduct the Actual Use Study in a
retail setting using overt advertising to attract study participants.
Recruitment in such a setting would have been extremely difficult both
because few of the women exposed to the advertising in a retail setting
would have actually needed emergency contraception at the time and
because those who did need it might be embarrassed to show an interest
in the product, given the setting.

The study procedures simulated anticipated Plan B OTC distribution in
that women received no medical screening or counseling prior to
receiving the product and no counseling on the product's use unless they
sought help from a healthcare professional. In an attempt to more
closely mimic an OTC population, the admission criteria intentionally
did not exclude women who had contraindications for the product or women
who had previously used any type of emergency contraception.

Women were required to self-select (identify themselves as needing
emergency contraception and enter the study site requesting it) and
self-administer the product (women received no counseling or instruction
outside of what was contained on and in the package). Although, in the
initial screening, women were told briefly about the study, no
information was provided about the product or its use. The prototype
product sample was sealed, as it would be in the OTC environment, so
that women had access only to the Drug Facts panel (Figure 2 and
Appendix 4) while making their decision to receive or not receive the
product. (Note: This limited amount of information was also the basis of
the Label Comprehension Study's first question regarding what Plan B is
used for). If a woman was eligible[^2] and chose to receive the product
after looking at it, she was given further information about the study
(not about the product) and asked to sign an informed consent form. If
she consented, she was asked to record additional background
information. The study product was then provided to her, along with a
Study Data Card (see Appendix 8) that she was asked to complete after
she used the product. Information regarding the timing of the sex act
and the ingestion of the two doses of Plan B were recorded on the Data
Card. All interactions with a healthcare professional at the time of
enrollment and subsequent to that time were noted, including the nature
of the questions asked.

Subjects who received the study product were contacted by phone or
in-person at the study site one week after receiving the product and
again after four weeks. Each woman was questioned about use of the
product, side effects and pregnancy. The information received by phone
was considered the principal source of information for the analysis.
Supplemental contacts were made if the subject's pregnancy status was
unclear, if she had unresolved adverse events at the last contact or if
she had used the product within the week before the last contact. At the
first contact following use of the product, the subject was asked to
mail the completed Study Data Card (see Appendix 8) to the study site.
After both contacts had been completed, the site provided compensation
to the subject (\$40 at the clinics; \$45 at the pharmacies). Pregnant
subjects were invited to call a WCC established pregnancy registry. This
registry was established solely for this study.

The results of the Label Comprehension Study showed that overall
subjects could adequately understand the language of the proposed OTC
label. The labeling of the study product used in the Actual Use Study
was nearly identical to the prototype product tested in the Plan B Label
Comprehension Study (see Appendix 4).

In an effort to evaluate repeat use, the study design did not limit the
number of times a woman could receive the product. Women were allowed to
enroll in the study as many times as they presented to the clinic or
pharmacy during the enrollment period. The enrollment period at each
site ranged from 35 to 95 days. At each re-enrollment, the subject
followed the same procedures as at the initial enrollment. Women were
not offered multiple packages at enrollment. However, as in an OTC
setting women were not prohibited from obtaining multiple packages upon
request. Women requesting emergency contraception for future use were
not excluded. To simulate OTC distribution, participants were required
to pay for the product.[^3]

[]{#__RefHeading___Toc56513709 .anchor}Figure 2: Instructions for Use
Printed on the Outside of the Plan B OTC Actual Use Study Label^\*^

![](media/image2.wmf){width="5.249305555555556in"
height="3.0083333333333333in"}

*\* Actual Size of the Label*

[]{#__RefHeading___Toc56513660 .anchor}4.3.2 Study Population

The sample size for the Actual Use Study was estimated to be 256
subjects who used Plan B. It was calculated to estimate the frequency of
the two primary study outcomes (contraindicated use and incorrect use)
with confidence intervals ± 5%. In these calculations, it was assumed
that both true proportions were 15%. To account for multiple confidence
interval estimations, the Bonferroni adjustment was applied, so that the
97.5% confidence limits were estimated rather than the traditional 95%
limits. The Bonferroni adjustment was appropriate because of the lack of
evidence for a correlation between the two behaviors of contraindicated
use and incorrect use. This calculation was conservative because it was
expected that the proportions of contraindicated and incorrect use would
be lower than 15%. In that case, to achieve the same level of precision
(**±** 5%), fewer subjects would have been required. To ensure diversity
of the study population and allow for subgroup analyses, target
enrollment was at least 450 subjects who each used Plan B at least one
time.

The analysis populations in the Actual Use Study were defined as
follows:

-   **Screened Cohort**: Includes all subjects screened in the study,
    with no exclusions (665 women).

-   **Enrolled Cohort**: Subset of the screened cohort, including only
    the subjects who received study product (585 women).

-   **Per-Protocol Cohort**: Subset of the enrolled cohort, excluding
    subjects who were enrolled with violations of any of the study
    admission criteria listed in the protocol (576 women).

-   **Lost to Follow-up Cohort**: Subset of the enrolled cohort,
    including all subjects for whom no follow-up information was
    provided (42 women).

Of the 665 women screened, 585 (88%) were enrolled in the study (i.e.,
left the study site with study product). Of the 80 women who were not
enrolled, 69 were not offered or declined to sign the written informed
consent, 3 did not want to be contacted during the study, 2 did not want
to participate, 1 changed her mind about even wanting to receive Plan B,
2 thought that the study was too long a duration, for 1 the information
was unknown and 2 others were deemed ineligible after they had already
signed the informed consent form (e.g., both stated they were not sure
they should receive emergency contraception). Of the 585 enrolled women,
576 (98%) were eligible to participate (Per-Protocol Cohort) and 9 were
enrolled into the study without the site realizing they were ineligible
(8 stated they were not sure they should receive emergency
contraception, and 1 did not come into the clinic to receive emergency
contraception) but have been retained in the enrolled cohort (they were
excluded from the per-protocol cohort).

Among the 585 women in the enrolled cohort, 542 (93%) completed at least
one follow-up contact, and one additional subject provided only her Data
Card\
(Appendix 8). The 42 subjects (7.4% of the Enrolled Cohort) who did not
provide any follow-up information constituted the lost to follow-up
cohort. A total of 513 (87.7% of the Enrolled Cohort) had at least two
follow-up contacts. The median time to first contact was 8 days (mean =
11.6 days). In the case of the second contact, 93% of those occurred 28
days or longer after enrollment with median time of 30 days (the
specified time for the one-month contact). In addition, a total of 336
study participants mailed in their Data Cards.

The 585 women enrolled in this study represent a broad spectrum of
socio-demographic characteristics and were very similar to the expected
OTC population (Table 15). The median age was 21 years with 5% aged 16
or younger. This compares with the estimated 6% of women of reproductive
age (14-44) who are in the 14 to 16 year age bracket (VHS 1997, U.S.
Census 2000, MMWR 2002). Racial/ethnic characteristics were as follows:
76% classified themselves as white, 10% as black or African-American,
and 14% classified themselves as Hispanic. These numbers are
representative of the racial/ethnic diversity of women of reproductive
age in the U.S. population. Note these are not mutually exclusive
racial/ethnic categories, the participants were given the opportunity to
classify themselves into multiple racial/ethnic categories, e.g., a
subject could call herself white, African American and/or Hispanic.

Of the women enrolled in the study, 13% had less than a high-school
education. The majority of study participants (65%) reported incomes of
less than \$35,000 a year, consistent with the young age distribution.
Barr expects that the population that eventually will purchase Plan B
OTC will differ from the general U.S. population in that it will likely
include fewer minority group women, low-income women, and young
adolescents since these women may be less aware of emergency
contraception as an option and may have less discretionary income with
which to purchase Plan B. Barr expects family planning clinics to
continue to be a major source of Plan B for women who need free
subsidized services.

[]{#__RefHeading___Toc56513703 .anchor}Table 15: Socio-Demographic
Characteristics of Screened and Enrolled Cohorts in the Actual Use Study
(% of each subset)

+-------------------------------------+----------+----------+----------+
| **Demographic Breakdown**           | **       | **       | **% U.S. |
|                                     | Screened | Enrolled | Women**  |
|                                     | Cohort** | Cohort** |          |
|                                     |          |          | **(Aged  |
|                                     | **(      | **(      | 14       |
|                                     | n=665)** | n=585)** | -44)\*** |
+-------------------------------------+----------+----------+----------+
| **Age (years)**                     |          |          |          |
+-------------------------------------+----------+----------+----------+
| 14-16                               | 4.8      | 5.0      | 9.2      |
+-------------------------------------+----------+----------+----------+
| 17-25                               | 75.9     | 74.4     | 26.8     |
+-------------------------------------+----------+----------+----------+
| 26-30                               | 12.8     | 14.0     | 15.5     |
+-------------------------------------+----------+----------+----------+
| 31-35                               | 4.1      | 4.1      | 16.2     |
+-------------------------------------+----------+----------+----------+
| 36-44                               | 2.4      | 2.6      | 32.2     |
+-------------------------------------+----------+----------+----------+
| Missing                             | 0        | 0        | \--      |
+-------------------------------------+----------+----------+----------+
| **Race**                            |          |          |          |
+-------------------------------------+----------+----------+----------+
| Asian                               | 6.5      | 6.3      | 4.3      |
+-------------------------------------+----------+----------+----------+
| American Indian/Alaskan Native      | 1.8      | 1.7      | 1.0      |
+-------------------------------------+----------+----------+----------+
| Black or African American           | 10.2     | 9.9      | 13.7     |
+-------------------------------------+----------+----------+----------+
| Native Hawaiian or other Pacific    | 1.7      | 1.7      | 0.2      |
| Islander                            |          |          |          |
+-------------------------------------+----------+----------+----------+
| White                               | 74.6     | 76.4     | 72.0     |
+-------------------------------------+----------+----------+----------+
| Missing                             | 8.0      | 6.7      | \--      |
+-------------------------------------+----------+----------+----------+
| **Marital Status**                  |          |          |          |
+-------------------------------------+----------+----------+----------+
| Single                              | 89.5     | 89.1     | \--      |
+-------------------------------------+----------+----------+----------+
| Married                             | 5.6      | 5.6      | \--      |
+-------------------------------------+----------+----------+----------+
| Divorced                            | 2.6      | 2.9      | \--      |
+-------------------------------------+----------+----------+----------+
| Separated                           | 2.1      | 2.2      | \--      |
+-------------------------------------+----------+----------+----------+
| Missing                             | 0.3      | 0.2      | \--      |
+-------------------------------------+----------+----------+----------+
| **Reported Highest Level of         |          |          |          |
| Education Completed**               |          |          |          |
+-------------------------------------+----------+----------+----------+
| 8^th^ grade or less                 | 0.5      | 0.3      | \--      |
+-------------------------------------+----------+----------+----------+
| 9^th^ to 11^th^ grade               | 13.8     | 13.0     | \--      |
+-------------------------------------+----------+----------+----------+
| High school/GED                     | 14.0     | 13.2     | \--      |
+-------------------------------------+----------+----------+----------+
| Technical school                    | 1.7      | 1.5      | \--      |
+-------------------------------------+----------+----------+----------+
| Some college                        | 48.3     | 49.6     | \--      |
+-------------------------------------+----------+----------+----------+
| Finished college                    | 15.9     | 16.2     | \--      |
+-------------------------------------+----------+----------+----------+
| Graduate school                     | 5.7      | 6.2      | \--      |
+-------------------------------------+----------+----------+----------+
| Missing                             | 0.2      | 0        | \--      |
+-------------------------------------+----------+----------+----------+
| **Household Income**                |          |          |          |
+-------------------------------------+----------+----------+----------+
| 0-15,000                            | 38.0     | 39.5     | \--      |
+-------------------------------------+----------+----------+----------+
| 15,001-25,000                       | 13.2     | 13.2     | \--      |
+-------------------------------------+----------+----------+----------+
| 25,001-35,000                       | 12.3     | 12.5     | \--      |
+-------------------------------------+----------+----------+----------+
| 35,001-45,000                       | 7.2      | 7.7      | \--      |
+-------------------------------------+----------+----------+----------+
| \>45,001                            | 10.7     | 10.6     | \--      |
+-------------------------------------+----------+----------+----------+
| Missing                             | 18.5     | 16.6     | \--      |
+-------------------------------------+----------+----------+----------+

*\* Data is from U.S. Census 2000.*

The participant characteristics of the 585 subjects who were enrolled in
the study (Enrolled Cohort) were almost identical to those of the
screened cohort. The per-protocol cohort also had similar
characteristics. Approximately 68% of the enrolled cohort had never been
pregnant before their first screening and more than 80% had no living
children. Forty percent had previously used emergency contraception;
13.8% had used it more than once. A total of 536 subjects (92% of the
Enrolled Cohort) reported having used a contraceptive method in the
month before admission into the study. Sixty percent indicated that they
had had sex without contraception at least once in that month (including
the act that prompted the subject's use of emergency contraceptive
pills). About 16% of the enrolled cohort reported irregular menstrual
cycles. Where information was provided, the median cycle length was 28
days.

Only 16% of the subjects who received the study product spoke with the
clinician or pharmacist at the study site after making their
self-selection. Most of the questions asked could have been answered in
an OTC setting by a pharmacist reading the\
Plan B label and/or proposed patient brochure. The most common questions
related to the safety of the product, including side effects and
contraindications, instructions for use, whether or not to take it with
food, or other questions about Plan B or other methods of contraception.

[]{#__RefHeading___Toc56513661 .anchor}4.3.3 Analysis of Primary Outcome
Variables of Plan B OTC Actual Use Study

[]{#__RefHeading___Toc56513662 .anchor}4.3.3.1 Contraindicated Use

Contraindicated use was defined as having occurred if the subject took
the pills contrary to any of the three warnings specified on the outer
package label:

#  *Warnings*

**Do not use:**

-   If you are already pregnant (because it will not work)

-   If you are allergic to any ingredient in Plan B

-   If you have unusual vaginal bleeding

When the product was provided using a simulated OTC approach, the
incidence of contraindicated use was extremely low (1.3%, 7 out of 523
classifiable cases). One subject was considered to have been pregnant at
the time of product use and 6 subjects had unexplained vaginal bleeding
before use of Plan B. None of the women reported that she had recognized
these situations prior to use of the product; therefore, none of the
contraindicated uses was determined to be deliberate. Only one of the
contraindicated uses (unexplained vaginal bleeding) occurred in a woman
under the age of 17. She was also the only contraindicated user with
less than a High School education. Three of the contraindicated uses
(all unexplained vaginal bleeding) occurred in women who had used
emergency contraception before. Of all six women who had unexplained
vaginal bleeding before using Plan B, one reported vaginal bleeding as
an adverse event after taking Plan B. Her vaginal bleeding ended two
days after she took Plan B.

[]{#__RefHeading___Toc56513663 .anchor}4.3.3.2 Incorrect Use

Incorrect use was defined as having occurred if the subject took the
pills contrary to the following dosing schedule indicated on the inner
and outer labels:

***Directions***

-   Take the first tablet as soon as possible but no later than 72 hours
    (3 days) after unprotected sex.

-   Take the second tablet 12 hours after you take the first tablet.

In the primary analysis of incorrect use, this schedule for correct use
was interpreted strictly: that is, if the first tablet was taken more
than 72 hours after the unprotected sex act, or if the second tablet was
not taken exactly 12 hours after the first tablet, the use was
considered incorrect. However, this definition may be unrealistically
strict in that it allows NO variation at all in the interval between the
two doses of medication, i.e., to be classified as having used the
product correctly, the subject would have had to report that she took
the second tablet exactly 12 hours after the first tablet, indicated by
recorded tablet ingestion times that were exactly 12 hours apart.

A total of 98% percent of the subjects (499 of the 509 who provided
usable information for the timing of both the sex act and the ingestion
of the first pill) reported taking their first pill no more than 72
hours following the sex act, with a median time of 36 hours. A total of
506 patients provided information on the timing of the sex act, timing
of ingestion of the first pill and timing of ingestion of the second
pill. Of these, 366 patients (72%) took both pills within timeframes
recommended by the label.

Further, in patients who recorded the timing of ingestion of both pills,
73.8% (398/540 with available data) of subjects recorded a time of
exactly 12 hours, 85.9% (464 subjects) recorded a time of between 11.5
and 12.5 hours, and 94.2% (508 subjects) recorded a time between 10 and
14 hours following the first dose.

[]{#__RefHeading___Toc56513664 .anchor}4.3.4 Analysis of Pregnancy
During Plan B OTC Actual Use Study

Since the dose and regimen proposed for OTC use are identical to the
R~x~ product, assessing the efficacy of Plan B was not a primary goal of
the Actual Use Study; however, pregnancies were analyzed to determine
the proportion of failures. Of the 540 subjects who were enrolled and
were confirmed to have taken Plan B during the study, it was determined
that 10 of them became pregnant after product use\
(Figure 3). No information on the pregnancy status was available for an
additional 14 subjects. Thus, the effective denominator of the number of
subjects at risk for pregnancy was 526. The proportion of women who may
have become pregnant after first use is 10 of 526 or 1.9% (95%
confidence interval 0.92%, 3.47%). These figures may represent a
conservative estimate of the failure rate of Plan B, as some of these
women may have become pregnant from coital acts before or after the act
that prompted use of the product.

All of the subjects who became pregnant took the first pill within 72
hours of having sex and the second 12 to 13 hours after the first. None
of these 10 participants took the study product more than once. Of the
ten pregnancies reported in this study, four ended in elective abortion
while the outcomes of the other six are unknown. Only one subject called
into the Pregnancy Registry. She reported an elective pregnancy
termination.

[]{#__RefHeading___Toc56513710 .anchor}Figure 3: Pregnancy Analysis in
Actual Use Study

![](media/image3.png){width="5.083333333333333in"
height="2.4895833333333335in"}

The proportion of subjects who became pregnant in the Actual Use Study
(1.9%) is not substantially higher than the proportion in the
levonorgestrel group of the WHO (#92908) pivotal clinical study (1.1%).
However, a direct comparison (Table 16) of pregnancy rates in the two
trials is complicated by differences in study designs and population
behaviors:

1.  In the WHO #92908 study, pregnancy tests were performed if menses
    following product use were delayed, whereas in the Actual Use Study,
    no pregnancy tests were performed except by the subjects themselves
    at their own discretion.

2.  The WHO #92908 study enrolled women who had had only one unprotected
    sex act, and the women were advised to not have additional sex in
    the enrollment cycle after admission; whereas the Actual Use Study
    did not have this restriction.

3.  The WHO #92908 study excluded women who had recently used hormonal
    contraception, whereas about one quarter of the Actual Use Study
    subjects did so.

[]{#__RefHeading___Toc56513704 .anchor}Table 16: Efficacy Results for
Actual Use Study and NDA Pivotal Study

+------------------------+----------------------+----------------------+
|                        | **Actual Use Study** | **WHO #92908**       |
|                        |                      |                      |
|                        | **(WCC/FHI 2002)**   | **(WHO 1998b)**      |
+------------------------+----------------------+----------------------+
| Number of women        | 526                  | 976                  |
+------------------------+----------------------+----------------------+
| Number of pregnancies  | 10                   | 11                   |
+------------------------+----------------------+----------------------+
| Pregnancy rate (%)     | 1.9                  | 1.1                  |
+------------------------+----------------------+----------------------+
| Number of              | \--                  | 11/76.3              |
| observed/expected      |                      |                      |
| pregnancies            |                      |                      |
+------------------------+----------------------+----------------------+
| Prevented fraction (%) | \--                  | 86                   |
+------------------------+----------------------+----------------------+

[]{#__RefHeading___Toc56513665 .anchor}4.3.5 Additional Results of the
Plan B OTC Actual Use Study

Of the 543 subjects who provided follow-up data after the first
screening, all reported that they had had sex in the month before the
first screening. Most (92% of the Enrolled Cohort) claimed to have use
some method of contraception in that month (Table 17): condoms (79%),
withdrawal (28%), oral contraceptive pills (22%) and/or spermicides
(9%). Sixty percent (60%) claimed to have had at least one sex act in
the month without contraception before enrollment.

A total of 336 (62%) of the 543 women who provided follow-up data
indicated that they had had sex after receiving study drug, only 20% of
whom reported to have a sex act without using any method of
contraception. The methods most commonly used during the follow-up
period were condoms (90%), oral contraceptive pills (21%), spermicide
(11%) and withdrawal (10%).

[]{#__RefHeading___Toc56513705 .anchor}Table 17: Contraceptive Methods
Used Before and After Receiving Plan B

  --------------------------- -------------------- ----------------------
  **Subjects who**:           **Provided follow-up **Indicated they had
                              information**        sex after receiving
                                                   drug**

                              N = 543              N = 336/543 (62%)

  **Contraceptive Method(s)                        
  Used:**                                          

  Condoms                     79%                  90%

  Withdrawal                  28%                  10%

  Oral Contraceptives         22%                  21%

  Spermicide                  9%                   11%
  --------------------------- -------------------- ----------------------

Analysis of the reported methods of contraception in the month prior to
enrollment and between enrollment and the last follow-up contact for
those who had sex in both intervals, slightly more (11%) of women
started using a more effective method compared with 8% who stopped using
a more effective method during at least some portion of these intervals.
Ten percent (10%) initiated condom use after receiving the product,
whereas only 5% used a condom at least once in the month before
enrollment, but not in the follow-up period after enrollment. Younger
subjects and those with less than high school education were more likely
to switch from a less to a more effective method after screening.

Only 6% of subjects consulted with a healthcare professional at a later
date. The most common reason for consulting a healthcare provider was
simply to inform him or her about product use. Other reasons included
medical problems or side effects, ongoing contraception, a positive
pregnancy test, questions about Plan B, repeat need for emergency
contraception or for a routine appointment.

Eight subjects used the product twice, and two used it three times
during the course of the study. The reason for each repeat use was
consistent with the indications for use described on the product label.

[]{#__RefHeading___Toc56513666 .anchor}4.3.6 Prior vs. Naïve Users

The relatively large number of prior users in the Actual Use Study
allowed useful comparisons between prior users of emergency
contraception and naive/never users. The analyses showed that women who
had been counseled and screened by a medical practitioner in the past
and those who presented for emergency contraception without the benefit
of such counseling (naïve users) did not differ significantly with
respect to contraindicated or incorrect use (Table 18), use of regular
contraception, or most other variables.

[]{#__RefHeading___Toc56513706 .anchor}Table 18: Contraindicated and
Incorrect Use Among Prior and Naïve Users of Emergency Contraception

  ----------------------------- -------------- -------------- ---------------
                                **Prior User** **Naïve        **Total^\*^**
                                               Users**        

  **Total Uses**                **N=213**      **N=327**      **N=540**

  Contraindicated Use           1.4%           1.2%           1.3%

                                                              

  Incorrect Use                 29.6%          23.5%          25.9%

  Deliberate                    1.9%           0.9%           1.3%

  Unintentional                 27.7%          22.6%          24.6%

  Correct Use                   66.7%          68.5%          67.8%

                                                              

  Following Instructions                                      

  1^st^ pill [\<]{.underline}   95.3%          90.5%          92.4%
  72 hrs. after sex                                           

  2^nd^ pill exactly 12 hrs     68.5%          73.7%          71.7%
  after the 1^st^                                             
  ----------------------------- -------------- -------------- ---------------

*\* Denominator includes subjects both with and without data available*

[]{#__RefHeading___Toc56513667 .anchor}4.3.7 Safety Results for the Plan
B OTC Actual Use Study: Adverse Events

Adverse events among subjects in the enrolled cohort were tabulated
(Table 19). Adverse events include all medical problems reported at
subject contacts or on Study Data Cards (see Appendix 8) after use of
the study product. For events reported at subject contacts, information
on various characteristics of the event was collected: including:
severity (mild, moderate or severe), seriousness (not serious or
serious), relationship to study drug (yes or no), specific complaint
(COSTART preferred term) and body system class. Study Data Cards
(Appendix 8) did not collect this information. Frequencies of adverse
events were also calculated for subgroups of subjects who used the study
product in a contraindicated or incorrect fashion.

Of the 540 subjects who used the current regimen of levonorgestrel 0.75
mg in the Actual Use Study, 46% (246 subjects) reported at least one
adverse event at either follow-up contact or on the Study Data Card
(Appendix 8). As seen in Table 19 abdominal pain was reported by 14.3%
(77 subjects), nausea and/or vomiting by 13.7% (74 subjects), headache
by 11.3% (61 subjects), and asthenia by 8.0% of women (43 subjects).

Subjects with contraindicated or incorrect use did not notably differ
from the enrolled cohort in frequency or nature of reported adverse
events. Three of the women whose use of the product was contraindicated
did not report any adverse events. For women who took the product
incorrectly, by the primary definition, 44% experienced an adverse
event, compared to 46% of the total enrolled cohort. Only four types of
adverse events were reported by more than 5% of those subjects with
incorrect use of Plan B: abdominal pain (12.7%), asthenia (8.5%),
headache (9.2%) and nausea and/or vomiting (12.0%).

[]{#_Ref55894900 .anchor}

Table 19: Percent of Subjects Reporting Adverse Events in Actual Use
Study (≥ 5% reported for at least one subset)[^4]

+------------------------------+------------+--------------+-----------+
| **Adverse Events**           | *          | **Subjects   | *         |
|                              | *Total\*** | With         | *Subjects |
|                              |            | Con          | With      |
|                              | *          | traindicated | Incorrect |
|                              | *(n=246)** | Use**        | Use**     |
|                              |            |              |           |
|                              |            | **(n=7)**    | **        |
|                              |            |              | (n=142)** |
+------------------------------+------------+--------------+-----------+
| Abdominal pain               | 14.3       | 14.3         | 12.7      |
+------------------------------+------------+--------------+-----------+
| Acne                         | 0.6        | 14.3         | 0.7       |
+------------------------------+------------+--------------+-----------+
| Asthenia                     | 8.0        | 0            | 8.5       |
+------------------------------+------------+--------------+-----------+
| Breast pain                  | 2.8        | 14.3         | 4.2       |
+------------------------------+------------+--------------+-----------+
| Headache                     | 11.3       | 28.6         | 9.2       |
+------------------------------+------------+--------------+-----------+
| Nausea and/or vomiting       | 13.7       | 14.3         | 12.0      |
+------------------------------+------------+--------------+-----------+
| Menstrual disorder           | 6.6^§^     | 0            | 0.7       |
+------------------------------+------------+--------------+-----------+
| Pharyngitis                  | 2.6        | 14.3         | 2.1       |
+------------------------------+------------+--------------+-----------+
| **Any adverse event**        | **45.6**   | **57.1**     | **43.7**  |
+------------------------------+------------+--------------+-----------+

> *\* Reported at follow-up contact or on Study Data Card.*
>
> *\*\* Reported at follow-up contact. Only events reported at follow-up
> contact were classified as being related to the product, or not.*
>
> *^§^ Menstrual disorder includes: lighter menstrual bleeding,
> menorrhagia, menstrual disorder and metrorrhagia.*

At subject contact, product users reported a total of 412 adverse
events. Of these, 352 (85%) were considered to be mild, and the rest
were moderate. None met the FDA definition of a serious adverse event
(see 21 C.F.R. §314.80(a)). One third (135 of 412 adverse events) were
treated with concomitant medication, either prescription or OTC. Only 8
subjects stated that their adverse events (hematuria, urinary
incontinence, urinary urgency, headache, abdominal pain, and vomiting)
could or might stop them from using the product in the future.

Of the 540 subjects who used the study product, 513 (95%) had a
menstrual period before the end of their study participation. The first
menstrual period of those who had periods started a median of seven days
after ingestion of the product (range 0--49 days). This pattern was not
substantially different in the subset of 22 subjects who were age 16 or
younger.

[]{#__RefHeading___Toc56513668 .anchor}4.3.8 Actual Use Study:
Conclusion

The Plan B OTC Actual Use Study was designed to provide information on
whether women seeking emergency contraception could self-select and use
the product appropriately and safely when it is labeled for OTC
distribution. The sample consisted of subjects of all races between the
ages of 14 and 44 years who would be likely to use Plan B in the OTC
setting. Subjects were asked to review the proposed Plan B package and
decide whether or not to receive the product, with no unsolicited
screening or counseling by a healthcare professional prior to using Plan
B.

Results in the Actual Use Study were consistent across all subgroups
examined. Potentially vulnerable groups such as less educated women and
minors were not substantially more likely to use the product in an
incorrect or contraindicated manner. In fact, incorrect use was lower
among subjects aged 16 years and younger than those aged 17 years and
older. These vulnerable groups also did not have higher risks of
pregnancy in this study.

When the findings of this study are compared to those of the pivotal
clinical trial for Plan B conducted by WHO (#92908), results are
remarkably similar. The distribution of reported intervals between doses
was almost identical (Table 20). In addition, the proportion of subjects
who became pregnant was similar.

[]{#__RefHeading___Toc56513708 .anchor}Table 20: Interval Between Pill
Doses in Actual Use Study and NDA Pivotal Clinical Trial

+----------------------------+-------------------+--------------------+
|                            | **Actual Use      | **WHO #92908**     |
|                            | Study**           |                    |
|                            |                   | **(Levonorgestrel  |
|                            | **(WCC/FHI        | group)\***         |
|                            | 2002)**           |                    |
+----------------------------+-------------------+--------------------+
|                            | **n=523**         | **n=974**          |
+----------------------------+-------------------+--------------------+
| Interval between doses:    |                   |                    |
+----------------------------+-------------------+--------------------+
| Less than 12 hours         | 52 (10%)          | 88 (9%)            |
+----------------------------+-------------------+--------------------+
| Exactly 12 hours           | 387 (74%)         | 720 (74%)          |
+----------------------------+-------------------+--------------------+
| More than 12 through 16    | 63 (12%)          | 127 (13%)          |
| hours                      |                   |                    |
+----------------------------+-------------------+--------------------+
| More than 16 hours         | 21 (4%)           | 49 (5%)            |
+----------------------------+-------------------+--------------------+

> \*Source: FHI reanalysis of data submitted in approved NDA 21-045 for
> Plan B (levonorgestrel) for emergency contraception. Numbers do not
> add to 100% due to rounding.

Women were allowed to enroll in the study as many times as they
presented to the clinic or pharmacy, although repeat use of the study
product was rare. Eight subjects used the study product twice over the
course of the study and two received it three times. Considering that
7.5% of sexually active U.S. women at risk of pregnancy who do not
desire to become pregnant use no contraception (Trussell 1998d), the
repeated need for the product in this study by 10 of 585 women (1.7%)
does not suggest any patterns of abuse. Although 40% of the Enrolled
Population reported prior use of emergency contraception, only 8%
reported use within the last three months and only 2% reported use
within the last month.

It would appear, therefore, that the results in the Actual Use Study not
only demonstrated that the subjects could adequately follow the stated
directions for use of Plan B as an emergency contraceptive but also that
they followed a pattern of use in a simulated OTC setting that mirrored
the pattern of use observed in the original NDA controlled study. The
value of the Actual Use Study is that it was conducted in a population
representative of women in the United States who would be among the most
identifiable target for access to Plan B as an OTC emergency
contraceptive.

[]{#__RefHeading___Toc56513669 .anchor}5 benefit/risk overview of plan b
as an otc emergency contraceptive

[]{#__RefHeading___Toc56513670 .anchor}5.1 Overview

Levonorgestrel has a more than 30-year history of use in contraception,
and its safety profile has been well characterized in the clinical
literature. The levonorgestrel regimen for emergency contraception is
currently approved in 101 countries. In 33 of these countries it is
currently sold without a prescription, by pharmacists, or over the
counter. A Gedeon Richter, Ltd. 0.75 mg levonorgestrel tablet,
manufactured since 1980 with only minor formulation changes, is
currently marketed in 70 countries. Clinical trials, medical literature,
and post-marketing surveillance by pharmacovigilance agencies have
provided a well-characterized safety profile. A substantial body of
evidence indicates that the safety profile of Plan B for use as
emergency contraception appears to pose no untoward safety concerns.
Experience with the prescription product since 1999 in the United States
has demonstrated a high level of safety. An evaluation of international
post-marketing adverse events also shows that "real-life" usage of
emergency contraception does not pose safety concerns.

 

[]{#__RefHeading___Toc56513671 .anchor}5.2 Risk Assessment of Plan B

The following have been identified by the sponsor as the major sources
of risk potentially associated with the use of OTC Plan B for emergency
contraception:

-   The first tablet is not taken within 72 hours of unprotected sex.
    The result would be a reduced probability of effectiveness. The
    recommended dosing regimen is to take the first tablet within 72
    hours after the sexual encounter to maximize efficacy. However,
    easier access to emergency contraception would be expected to
    optimize the ability to take the pills as soon as possible after
    unprotected intercourse

-   The second tablet is taken simultaneously with the first, or is
    taken at some point after the first tablet is taken but less than 12
    hours after. Evidence from clinical trials suggests that although
    such use is not approved and is not supported by the data, in the
    New Drug Application, taking the second tablet simultaneously with
    the first or in advance of 12 hours would not adversely affect the
    efficacy of the product. (WHO 2002).

-   The second tablet is not taken at all, or is taken at some point
    beyond 12 hours after the first tablet. The result could be a
    reduced probability of effectiveness. Evidence from clinical trials
    does not show any safety risk to the patient if the second tablet is
    not taken at all, or is taken more than 12 hours after the first.
    Indeed, substantial efficacy was still obtained in earlier trials
    involving the use of a single 0.75 mg levonorgestrel tablet (WHO
    1987, He 1991, WHO 2000a).

-   The patient could suffer some labeled adverse event such as nausea,
    stomach pain, headache, and dizziness or breast tenderness. However,
    these adverse events are safer than a potential unintended pregnancy
    or abortion.

-   Plan B is contraindicated in patients who are pregnant, are having
    unexplained vaginal bleeding, or are allergic to levonorgestrel or
    any other ingredients in\
    Plan B. However, each of these contraindications should be easy for
    the consumer to self-identify. In addition, there is no evidence
    that Plan B would harm a pregnant woman or a developing fetus if the
    product is taken accidentally during early pregnancy (Grimes 2001,
    Bracken 1990). Regarding unexplained vaginal bleeding, there are no
    known conditions that cause vaginal bleeding that will be worsened
    in the short term by the use of combined oral contraceptives, so
    there should be even less concern with a progestin-only method (WHO
    2000b).

-   Plan B could be used on a regular basis in place of a method of
    contraception indicated for regular use. Plan B is intended only as
    an emergency contraceptive. It is not intended for regular use.
    However, the safety of repeat or frequent use of 0.75 mg
    levonorgestrel tablets has been investigated in several studies.
    These studies have shown that repeated use, even in a single
    menstrual cycle, is not associated with serious or lasting side
    effects (WHO 2000a, He 1991, Bhattacharjee 1987).

-   Plan B could be used "too" frequently. What constitutes "too"
    frequently is subjective. The indication for Plan B implicitly
    includes repeated use if unprotected sex is repeated. If unprotected
    sex occurs frequently, however, the appropriate course is adoption
    of a method of contraception indicated for regular use, not adoption
    of Plan B for regular use.

-   Consumers may believe that Plan B can protect against HIV or other
    Sexually Transmitted Infections "STIs", and as a result may abandon
    the use of condoms or use them less regularly. The data for the Plan
    B Label Comprehension Study, however, show that very high
    percentages of consumers, from all demographic groups, who have read
    a Plan B OTC prototype label understand that it does not protect
    against transmission of HIV/AIDS or other STIs.

-   The OTC availability of, and education around, Plan B as an
    emergency contraceptive could lead to increased risky behavior
    (i.e., unprotected sex) by consumers who believe that Plan B can
    protect them from unwanted pregnancy without having to use a regular
    contraceptive. However, a large, randomized, controlled trial in
    Great Britain demonstrated that education about emergency
    contraception did not increase sexual activity among young people
    (Graham 2002). In addition, many studies provide evidence that
    advanced provision of emergency contraception does not increase the
    incidence of unprotected sex (Raine 2000, Belzer 2003, Jackson
    2003). Finally, the Plan B Actual Use Study actually showed a
    decrease in the proportion of the Enrolled Population who had at
    least one sex act without contraception, from 60% in the month
    before the first screening to just 20% after the first screening
    (WCC/FHI 2002).

 

[]{#__RefHeading___Toc56513672 .anchor}5.3 Benefits of OTC Plan B

The following have been identified by the sponsor as the major potential
benefits associated with the use of OTC Plan B for emergency
contraception:

-   There are 3 million unintended pregnancies in the U.S. each year,
    with about half ending in abortion. Awareness and access to Plan B
    should greatly decrease the numbers of unintended pregnancies, and
    subsequent abortions.

-   Plan B is effective in reducing the incidence of unwanted pregnancy
    after a single act of unprotected mid-cycle coitus from 8% to 1%, a
    reduction of 89%.

-   Plan B needs to be used within 72 hours of unprotected sex. In
    addition, a combined analysis of the Yuzpe and Plan B regimens found
    that each 12 hours of delay reduced efficacy by about 50% (p=0.02)
    (Piaggio 1999). OTC access will allow women to acquire Plan B most
    expeditiously.  

-   Plan B is associated with a limited number of side effects, all of
    which are self-limited and not life threatening when compared to the
    risks associated with pregnancy or surgical abortion.  

-   Plan B does not adversely impact a pregnancy once the process of
    implantation has begun.  

-   If Plan B is ineffective, the long-term outcome is no different than
    if it had not been used at all.  

-   Based on the data presented in the sNDA, women were able to self
    diagnose, administer the product properly, and seek follow-up when
    needed.  

-   Easier access to emergency contraception would be expected to
    optimize the ability to take the pills as soon as possible after
    unprotected intercourse. With OTC access, women will not have to
    first contact a healthcare provider for a prescription.

-   OTC availability, along with increased awareness, will most
    effectively reduce the number of unintended pregnancies and
    abortions---important public health goals.  

-   Women will not have to discuss what may be an embarrassing situation
    with a third party.  

-   More than 50% of U.S. women presenting for elective abortion were
    using a method of contraception in the month they became pregnant,
    and only 1.3% reported using EC (Jones 2002b).  

-   Trussell et al. (1992b) estimate that wider use of EC could in
    theory reduce the number of unintended pregnancies and could reduce
    the overall number of abortions.

[]{#__RefHeading___Toc56513673 .anchor}5.4 Discussion and Conclusions --
Risks vs. Benefits

Removing the prescription requirement for Plan B coupled with increasing
awareness of emergency contraception will help ensure that Plan B plays
a larger role in the reduction of unintended pregnancy and interruption
of pregnancy --- important public health goals. OTC sale of Plan B
presents no serious safety issues. Efficacy of the product is likely to
be the same, or better given more timely access to the product. Based on
the results of the OTC studies conducted by the sponsor, a growing body
of literature, and foreign marketing experience, the risk of unintended
health consequences also appears to be minimal. There is no evidence to
suggest that American women will abuse Plan B as an OTC product.

In the sponsor's OTC studies, women were able to understand the proposed
labeling regardless of age, race, ethnicity, educational attainment or
medical literacy. Contraindicated use and repeat use were both low. No
negative impact was observed on regular contraceptive use. Other
supporting studies in which women self-diagnosed their need for
emergency contraception and used it without medical oversight \-- often
many months after receiving counseling \-- provide further evidence that
Plan B can be used safely, effectively and appropriately without medical
supervision. The results also suggest that most women do not abandon
regular contraception or engage in more risky sexual behavior if
emergency contraception is readily at hand. The UCSF results (UCSF
2003b) could suggest that in particularly vulnerable populations prone
to risky sexual behavior, easy cost-free access to emergency
contraception may marginally increase some types of risk-taking. It
cannot be assumed that OTC sale of Plan B in retail pharmacies would
have a similar impact, however, since users would be required to pay for
the product and Plan B would be at least as expensive (i.e., the
proposed single-use package) as routine forms of birth control.
Pragmatically, condoms and even oral contraceptives are a cheaper
alternative. The small increases in unprotected sex and consistent
condom use observed in the UCSF Emergency Contraception study (2003b),
were not observed in the Glasier *et al.* (1998c), Raine *et al.*
(2000), or Belzer *et al.* (2003) studies. All of the studies confirm
that easier access to the method increases the likelihood of use
following unprotected sex.

Plan B is in every respect an appropriate candidate for OTC sale. It
meets or exceeds the safety and efficacy standards required of other OTC
pharmaceutical products:

-   The drug product is very safe. There are no reports of deaths and
    few reports of serious adverse events in over 20 years of use for
    regular postcoital contraception and emergency contraception.

-   There is no evidence that Plan B would harm a pregnant woman or
    would harm a developing fetus if the product is accidentally taken
    during early pregnancy.

-   Side effects of Plan B are well-characterized, generally mild or
    moderate and self-resolving. Side effects rarely require medical
    intervention.

-   Plan B has few contraindications, all of which should be easy for
    the consumer to identify. Contraindicated use is unlikely to raise
    any safety problems.

-   Use by adolescents, including young adolescents raises no safety
    concerns.

-   Plan B is not addictive.

-   Overdosing is unlikely, since Plan B is packaged as a single course
    of treatment.

-   Instructions for use of Plan B are simple, and all users follow
    exactly the same regimen.

-   Incorrect use would not present any safety problems.

-   To date, there is no evidence that occasional use of Plan B
    increases the risk of ectopic pregnancy, even though chronic use of
    progestin-only contraceptives does appear to increase the risk.
    There is no reason to expect chronic use of Plan B.

-   No medical screening is required to use Plan B as the indication for
    use and the contraindications are easily recognized by a woman
    herself, without the need for a provider.

-   Medical screening by a healthcare provider does not typically
    identify women more likely to experience side effects, and does not
    prevent any side effects from occurring. It does not increase the
    safety of the regimen.

[]{#__RefHeading___Toc56513674 .anchor}6 plan b: Convenient Access,
Responsible Education Program

[]{#__RefHeading___Toc56513675 .anchor}6.1 Introduction

Barr has carefully constructed the CARE^SM^ ([C]{.underline}onvenient
[A]{.underline}ccess, [R]{.underline}esponsible [E]{.underline}ducation)
Program to help ensure that Plan B will be used responsibly and
appropriately as outlined in the proposed OTC labeling. Although Plan B
is under consideration as an OTC product (meaning that it can be used
safely and effectively without professional intervention), the sales and
marketing plan has been designed to limit the availability of Plan B, to
the extent practical, to pharmacies and clinics, and to educate
healthcare professionals and consumers regarding the availability and
responsible use of Plan B. The need to take Plan B in as timely a manner
as possible dictates that any responsible marketing program not only
address healthcare professionals but also include extensive consumer
education and direct access components. Thus, the CARE^SM^ program
contains elements that include an appropriate consumer education
component. In addition, the sponsor will work closely with chain
pharmacies to ensure that they will carry Plan B and provide access to
it in a responsible manner. Data suggests that there are several
critical issues currently limiting access to Plan B:

-   The prescription requirement delays timely access to Plan B;

-   Pharmacies may not routinely stock Plan B;

-   Awareness of the availability of Plan B is lacking among healthcare
    professionals as well as women of childbearing age, and

-   Access to accurate sources of information about the product is
    limited.

The CARE^SM^ program is intended to address these issues by providing
sources of accurate and responsible information to both healthcare
providers and consumers. It is also designed to provide a framework for
pharmacies to ensure availability of Plan B when sought by knowledgeable
consumers.

Four core elements of CARE^SM^ contribute to the achievement of program
objectives.

-   [Labeling/Packaging/Informational toll free number]{.underline} (to
    provide essential information to consumers in an accessible,
    easily-understood format),

-   [Education]{.underline} (to provide information intended to educate
    physicians, pharmacists and nurse practitioners and to provide
    healthcare practitioners with educational materials that they can
    supply to their patients to stimulate discussion.),

-   [Distribution]{.underline} (to ensure, to the extent practical, that
    Plan B will be available only in retail operations with pharmacy
    services and clinics and in a manner which allows easy access by the
    consumer to a pharmacist or other healthcare professional should
    questions arise), and

-   [Monitoring]{.underline} (to evaluate the effectiveness of the
    program and make adjustments as appropriate)

[]{#__RefHeading___Toc56513676 .anchor}6.2 CARE^SM^ Program Objectives

The CARE^SM^ program is designed to promote appropriate and responsible
use of Plan B by achieving the following objectives:

1.  To ensure that consumers and healthcare professionals understand
    what emergency contraception is and when it can and should be used
    safely and effectively.

2.  To ensure that consumers and healthcare professionals understand how
    to obtain Plan B in a timely manner.

3.  To clearly communicate that Plan B is for use only as an emergency
    contraceptive, and that it should not to be used as a routine form
    of contraception.

4.  To encourage the responsible use of Plan B and to encourage ongoing
    dialogue between healthcare professionals and consumers regarding
    responsible behaviors relating to contraception.

5.  To provide consumers with information needed to decide whether their
    use of Plan B would be appropriate.

6.  To provide additional resources to assist populations with special
    needs, such as low literacy populations, to make this decision
    correctly.

7.  To provide healthcare professionals with the information they need
    to guide their patients in purchasing and using the product, and
    encourage dialogue when appropriate.

8.  To provide retailers with the necessary information for both
    pharmacists and consumers, product packaging and labeling to
    merchandise Plan B at point of purchase to facilitate the provision
    of information without impeding access.

[]{#__RefHeading___Toc56513677 .anchor}6.3 Labeling/Packaging

The Plan B labeling is being developed to provide clear and
comprehensive communication of the key messages outlined above, and to
make known additional sources of information. Plan B is packaged as a
single course of therapy (two tablets) and will be priced in a manner
that reinforces appropriate usage as an emergency contraceptive. Plan B
packaging is being designed to improve readability, ease of use and
compliance. Packaging will include information designed for the
consumer, including those with low-literacy, on the need to use routine
forms of birth control. Materials will also continue to inform women
clearly about the lack of effectiveness against STI/HIV.

[]{#__RefHeading___Toc56513678 .anchor}6.3.1 Core messages

The Plan B labeling has been designed and tested to ensure that it
communicates the basic messages related to appropriateness and
responsible use, outlined in the objectives above:

-   Plan B is to be used only by women of childbearing potential

-   Plan B is intended only for emergency contraception

-   Plan B does not substitute for a regular form of contraception

-   Plan B does not protect against sexually transmitted diseases

-   Plan B must be started as soon as possible within 72 hours of
    unprotected sexual intercourse

-   Following the directions for use enhances Plan B's effectiveness

-   Plan B will not be effective if you are already pregnant

[]{#__RefHeading___Toc56513679 .anchor}6.3.2 Labeling refinements

Based on the results of the Label Comprehension Study, the sponsor has
proposed several refinements to enhance communication of these key
messages in the most recent version of the OTC labeling (Appendix 5). In
addition, the sponsor will add the following features to the labeling
and packaging as part of the CARE^SM^ program:

-   A larger outer package will be developed. Except for size, this
    package will be identical to the OTC package proposed in the sNDA
    (Appendix 5). This change will allow an increase in the font size
    throughout the labeling to improve readability and make the
    information more inviting.

-   A card will be included in the package to allow women to record the
    time of the initial dose and the projected time of the second dose.
    Doing so will encourage appropriate dosing, with the second tablet
    to be taken 12 hours after the first.

-   The labeling will direct users to a 24 hour toll free number staffed
    by a healthcare professional if they have any questions or concerns.

-   The labeling will direct users to a website for additional
    information.

-   Information will be provided reminding women that Plan B is not a
    routine form of birth control.

-   Clarifying information will be included in a patient leaflet insert,
    which will also provide information about contraceptive choices and
    STI's. The user will be encouraged to consult her healthcare
    professional for assistance in choosing a routine contraceptive
    method.

[]{#__RefHeading___Toc56513680 .anchor}6.3.3 Additional sources of
information

Information will be available at any time during the purchase and
product use cycle. A toll-free number, staffed by healthcare
professionals 24 hours a day will be available. The Plan B website will
also provide information to more information while maintaining consumer
privacy. The phone number and website address will be clearly identified
on both the outside of the package and the interior labeling.

[]{#__RefHeading___Toc56513681 .anchor}6.4 Education

Given the very low levels of awareness of the availability of emergency
contraception, the CARE^SM^ Program provides for an intensively
educational approach to the introduction of Plan B as an OTC product.
Barr is proposing an educational program that will initially focus on
healthcare professionals. The program will assist healthcare providers
in developing an adequate knowledge base so that they can provide
responsible and accurate counseling to patients.

Efforts directed to raising consumer awareness of the product and its
appropriate use will follow appropriate professional education programs.
The educational materials will address not only Plan B but will
encourage healthcare professionals to urge users to adopt routine forms
of contraception and avoid reliance on Plan B as their primary form of
birth control.

[]{#__RefHeading___Toc56513682 .anchor}6.4.1 Educational Program to
Healthcare Professionals.

Plan B will be introduced and explained to healthcare professionals to
raise awareness and knowledge levels as to emergency contraception.
Given the current lack of understanding of emergency contraception, this
program is intended to ensure that healthcare professionals are prepared
to support their patient populations.

1.  Physicians, physician assistants, nurse practitioners, and their
    staffs, and pharmacists are the primary audiences for this
    educational program. Pharmacists are especially important because
    they will need to be prepared to answer questions at the point of
    purchase. Programs will include continuing education by certified
    professionals and educational materials (including websites and toll
    free numbers) that can be accessed easily and at anytime. The
    sponsor will make available to the state boards of pharmacy
    continuing education programs for use at annual meetings and other
    regional programs. The sponsor will also encourage state boards of
    pharmacy to provide information to their members regarding the
    availability and appropriate use of Plan B.

2.  The sponsor's sales force for female healthcare products consisting
    of approximately 250 sales representatives will visit the offices of
    approximately 30,000 physicians, mostly Ob/Gyn's. The sales
    representatives will provide materials targeted for consumers.
    Physicians, physician assistants and nurse practitioners will be
    asked to distribute the materials to patients. Materials will
    encourage patients to discuss any questions they have about
    emergency contraception or the specific use of Plan B with their
    physician or the nurse practitioner. Efforts to reach healthcare
    professionals to reinforce these messages will continue indefinitely
    as part of the sponsor's ongoing professional communications
    program. The sponsor also will work with the relevant healthcare
    professional associations to provide programming and materials to
    reach those healthcare providers who will not be reached personally.

3.  All materials for consumers and healthcare providers will be tested
    through research and field testing to ensure communication
    objectives are met.

[\
]{.underline}[]{#__RefHeading___Toc56513683 .anchor}6.4.2 Educational
Campaign to Consumers

An information campaign to consumers will commence once the healthcare
professional audience has been introduced to the product. This consumer
education campaign is anticipated to begin about six months following
product launch.

1)  The campaign will be designed to convey critical awareness and
    educational messages as well as information about product
    availability. The intent will be to make consumers aware of the
    availability of emergency contraception and its appropriate use.

2)  The campaign will be designed to appeal to women age 17 to 44.

    a.  The language and visuals used will be appropriate and of
        interest to this age group. New promotional materials will be
        provided for comment to FDA during the development process and
        will be tested to ensure appropriate communication according to
        current practices*.*

    b.  Media placements that appeal to teen/adolescent audiences will
        not be used.

[]{#__RefHeading___Toc56513684 .anchor}6.4.3 Media Coverage

The sponsor is anticipating the potential for media coverage of the
December advisory panel meeting and the FDA's subsequent decision on the
sNDA. The sponsor will develop comprehensive media briefing materials
that emphasize the appropriate and responsible use of emergency
contraception. Company spokespersons will be media trained to ensure
strong and consistent communication of the appropriate messages,
consistent with the commitments above related to the tone and approach
to be taken with consumers.

[]{#__RefHeading___Toc56513685 .anchor}6.5 Distribution

The sponsor believes that in the interest of responsible usage (and in
recognition of the circumstances of the need for emergency
contraception), Plan B should be available in those retail outlets that
typically sell a broad range of OTC medications and that have pharmacy
services staffed with pharmacists (or, in the case of clinics, other
healthcare professionals) during normal business hours to answer
questions.

1.  The sponsor will sell Plan B directly to drug wholesalers, clinics,
    or retail chains and stores with valid pharmacy or drug wholesaler
    licenses. The sponsor will recommend, but cannot legally require,
    that Plan B be sold only in retail pharmacies, or other stores with
    a pharmacy on-site, such as food super stores and mass
    merchandisers. The sponsor will also recommend that Plan B is put on
    shelves near the pharmacy or within the line of sight of the
    pharmacist. Upon request, the sponsor will also make available for
    retail use. Product information to be placed in merchandising
    display units*.*

2.  The sponsor will recommend to all customers who purchase the product
    directly from the sponsor that they limit secondary distribution to
    consumers in clinics and retail outlets that have a pharmacy

3.  Plan B will continue to be made available to clinics (Planned
    Parenthood and government clinics). Doing so will enable the clinic
    population to obtain the product in an environment that provides
    easy access to professional contact and counseling.

[]{#__RefHeading___Toc56513686 .anchor}6.6 Monitoring

The sponsor intends to monitor trends in the use of emergency
contraception to evaluate the effectiveness of the CARE^SM^ program,
will make adjustments as appropriate. Monitoring will be accomplished in
several ways, with information gathered from both healthcare
professionals and consumers.

Monitoring actual use of Plan B is complex due to the difficulties
inherent in identifying women who have purchased the product and in
gathering useful, generalizable information. Consequently, the
monitoring component will rely on a variety of sources intended to
provide trend data, observational data, and signals of program
effectiveness and potential problems. Monitoring components will include
the following:

1\. A survey or surveys of a subset of healthcare professionals (e.g.
OB/GYN, family practice, pharmacists, nurses, family planning and health
clinic personnel) annually to determine:

-   Attitudes toward and experience with patients' usage of Plan B

-   Trends among emergency contraception users within their patient
    population (especially source of awareness, repeat use, use instead
    of more effective forms of contraception, acquisition of STIs, etc.)

-   Nature of interactions with Plan B users (Does the contact with the
    healthcare professional occur prior to product usage? after usage?
    Are the women in search of contraceptive counseling? What types of
    side effects are being seen in use?)

-   Areas where additional information is needed in the marketplace, as
    identified by the questions raised by the users

2\. Through collaboration with established professional groups and
pharmacy boards, other audiences may be surveyed to gather information
that could help evaluate the CARE^SM^ program and provide signals of
problems associated with patients' understanding of the purpose and
proper use of Plan B:

-   College student health clinics

-   Sex education teachers and counselors

-   Reproductive health professionals

> The information derived from these audiences is anticipated to be
> based on a small number of reliable contacts and therefore will need
> to be interpreted with care.

3.  Using relevant survey data regularly collected by others (e.g. CDC
    BRFSS, YRBSS, NGO surveys) the sponsor will monitor for potential
    indicators that Plan B is being used in an inappropriate manner.
    Where existing surveys do not include relevant data, the sponsor
    will seek inclusion of appropriate questions. Potential areas of
    analysis include evaluating possible correlations between:

    -   increases in STIs in areas with high Plan B sales;

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    -   increases in pregnancy and/or abortion rates in areas with high
        Plan B sales

    -   The sponsor recognizes that the use of these sources may not
        give timely enough data to evaluate the CARE^SM^ program in the
        short term. However, the commitment to monitoring extends beyond
        the initial stages of product introduction, and working with
        data sources to enhance collection of data relevant to use of
        Plan B will be ongoing.

4\. Gathering data from actual users of Plan B is difficult because the
number of users will be relatively small and because the decision to use
emergency contraception is a private and emotional one. Women choosing
to use the product are expected to wish to remain anonymous and are
entitled to maintain their privacy. Nevertheless, the sponsor will work
with a variety of sources in an effort to obtain and analyze consumer
data to assess the effectiveness of the CARE^SM^ program elements. The
primary focus of this component will be:

-   Foundations and Nongovernmental Organizations (NGOs) that conduct
    surveys on reproductive health issues. It is hoped that these
    studies can provide a sufficient base of Plan B users to determine
    and evaluate what impact, if any, the OTC availability of Plan B has
    on trends in the data (i.e. pregnancy rate, Plan B usage, abortion
    rate, acquisition of STIs, etc.)

The sponsor will work with the FDA to establish reporting formats and
schedules in order to ensure that data and information on program
effectiveness and changes are available on a timely basis.

[]{#__RefHeading___Toc56513687 .anchor}6.7 Summary and Conclusions

The sponsor recognizes that in order for Plan B to make a contribution
to the public health through OTC status, it is essential that the
product be marketed responsibly and used appropriately. The sponsor has
designed the CARE^SM^ Program to help achieve these objectives. Through
CARE's combination of education, distribution and marketing features,
Plan B will be substantially more accessible to those women for whom its
use is indicated, while monitoring will help the sponsor and the FDA
assess the impact of the program and take steps to improve it where
appropriate. The packaging and labeling, together with strong
relationships with healthcare professionals, professional organizations
and the FDA, will provide further reinforcement for the safe and
effective use of Plan B. The avoidance of inappropriate messages and
media placements will help ensure appropriate and consistent
information. Consumer information about product use and the importance
of contraceptive choices will help preclude the need for Plan B. The
CARE^SM^ program is a unique approach to OTC marketing and the sponsor
looks forward to working with the FDA to finalize key components and
establish reporting guidelines.

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    pills: a simple proposal to reduce unintended pregnancies. *Fam
    Plann Perspect*. 1992b; 24:269-273.

30. Trussell J, Ellertson C, Dorflinger L. Effectiveness of the Yuzpe
    regimen of emergency contraception by cycle day of intercourse:
    implications for mechanism of action. *Contraception*.
    2003c;67:167-171. (Preprint Trussell 2002)

31. UCSF. University of California, San Francisco. Results of the
    analysis of provision of emergency contraception to women enrolled
    in the study prior to December 31, 2001: Pharmacy access and advance
    distribution evaluation. Study #H9738-18501-02. Report prepared by
    PinneyAssociates. January 30, 2003b.

32. Ugocsai G, Rózsa M, Ugocsai P. Scanning electron microscopic (SEM)
    changes of the endometrium in women taking high doses of
    levonorgestrel as emergency postcoital contraception.
    *Contraception*. 2002;66:433-437.

33. United States Census Bureau. U.S. Summary: 2000. Census 2000
    Profile. Issued July 2002.

34. Van Look PFA, von Hertzen H. Emergency contraception. *Br Med Bull*.
    1993;49: 158-170.

35. van Royen AR, Calvin CK, Lightner CR. Knowledge and attitudes about
    emergency contraception in a military population. *Obstet Gynecol*.
    2000;96:921-925.

36. VHS. Fertility, Family Planning, and Women\'s Health: New Data From
    the 1995 National Survey of Family Growth. *Vital and Health
    Statistics*. Series 23. No. 19. May 1997. Available at:
    <http://www.cdc.gov/nchs/data/series/sr_23/sr23_019.pdf>. Accessed
    November 12, 2003.

37. WCC/FHI, Women's Capital Corporation and Family Health
    International. Plan B Over-the-Counter Label Comprehension Study
    Report. FHI Study #9728. Final Study Report. November 5, 2001.

38. WCC/FHI,Women's Capital Corporation and Family Health International.
    Plan B OTC Actual Use Study. Phase 3. Non-comparative case series
    study of Plan B levonorgestrel emergency contraceptive pills
    provided using a simulated over-the-counter approach. FHI Study
    #9727. Final Study Report. 2002. (Updated 2003)

39. Wells ES, Hutchings J, Gardner JS, et al. Using pharmacists in
    Washington State to expand access to emergency contraception. *Fam
    Plann Perspect*. 1998;30:288-290.

40. WHO #92908. Report of the pivotal study: A prospective, randomized,
    multi-center study to compare the Yuzpe regimen with levonorgestrel
    in emergency postcoital contraception. November 15, 1998. Published.
    Task Force on Postovulatory Methods of Fertility Regulation.
    Randomised controlled trial of levonorgestrel versus the Yuzpe
    regimen of combined oral contraceptives for emergency contraception.
    *Lancet* 1998b;352:428-433.

41. WHO Task Force on Post-Ovulatory Methods for Fertility Regulation.
    United Nations Development Programme/ United Nations Population
    Fund/World Health Organization/World Bank Special Programme of
    Research, Development and Research Training in Human Reproduction.
    Efficacy and side effects of immediate postcoital levonorgestrel
    used repeatedly for contraception. *Contraception* 2000a; 61:
    303-308.

42. WHO Research Group on Post-ovulatory Methods of Fertility
    Regulation. Published. von Hertzen H, Piaggio G, Ding J, et al. Low
    dose mifepristone and two regimens of levonorgestrel for emergency
    contraception: a WHO multicentre randomised trial. *Lancet*. 2002;
    360:1803-1810.

43. Wilcox AJ, Weinberg CR, Baird DD. Timing of sexual intercourse in
    relation to ovulation: effects on the probability of contraception,
    survival of the pregnancy, and sex of the baby. *New Engl J Med*.
    1995;333:1517-1521.

44. Wu S, Wang C, Wang Y. \[A randomized, double-blind, multicentre
    study on comparing levonorgestrel and mifepristone for emergency
    contraception\] \[Chinese\]. *Zhonghua Fu Chan Ke Za Zhi*.
    1999;34:327-330. \[Full text in Chinese available upon request\]

45. Yeung WSB, Chiu PCN, Wang CH, Yao YQ, Ho P-C. The effects of
    levonorgestrel on various sperm functions. *Contraception*.
    2002;66:453-457.

46. Downing D. Pharmacist prescribing of emergency contraception: the
    Washington State experience. Emergency contraception the
    pharmacist's role. *APhA Special Report*. Available at:
    http://www.pharmacist.com/pdf/emer\_ contra.pdf Accessed on November
    12, 2003

 

APPENDIX 1: Mechanism of Action

![](media/image4.png){width="5.559722222222222in"
height="8.096527777777778in"}

![](media/image5.png){width="5.909722222222222in"
height="8.399305555555555in"}

> **APPENDIX 2: Label Comprehension Questions/Questionnaire**
>
> ![](media/image6.png){width="5.741666666666666in" height="6.91875in"}
>
> ![](media/image7.png){width="5.740277777777778in"
> height="7.507638888888889in"}
>
> ![](media/image8.png){width="5.74375in" height="7.169444444444444in"}
>
> ![](media/image9.png){width="5.741666666666666in"
> height="7.331944444444445in"}
>
> ![](media/image10.png){width="5.7444444444444445in"
> height="7.1097222222222225in"}
>
> ![](media/image11.png){width="5.742361111111111in"
> height="6.815277777777778in"}
>
> ![](media/image12.png){width="5.749305555555556in"
> height="4.883333333333334in"}
>
> ![](media/image13.png){width="5.748611111111111in" height="7.24375in"}
>
> **Results of Individual Question Responses from the Label
> Comprehension Study Questionnaire by Age Group (All 656 Eligible
> Subjects)**

  --------------------------------------------------------------------------------------------------------
  **Question**                                         **12-16      **17-25      **26-50      **Total\
                                                       Years\       Years\       Years\       (N=656)**
                                                       (N=76)**     (N=355)**    (N=225)**    
  -------------- ------------------------------------- ------------ ------------ ------------ ------------
  7:             Without looking at the label, tell me 71.1^\*\*^   83.4^\*\*^   89.3^\*\*^   84.0^\*\*^
                 what Plan B is used for?                                                     

                 Contraception After Sex\* (Correct)   28.9         47.6         46.7         45.1

                 Contraception (Acceptable)            42.1         35.8         42.7         38.9

  8:             Is Plan B the same as ordinary birth  73.7         81.1         85.3         81.7
                 control pills or is it different from                                        
                 ordinary birth control pills?                                                
                 (DIFFERENT)                                                                  

  9:             According to the label, should Plan B 77.6         87.0         85.3         85.4
                 be used as regular birth control?                                            
                 (NO)                                                                         

  10:            After unprotected sex, when is the    82.9^\*\*^   82.3^\*\*^   77.3^\*\*^   80.6^\*\*^
                 best time to take the first tablet?                                          

                 ASAP and w/in 72 hrs/3days (Correct)  13.2         25.1         24.4         23.5

                 ASAP (Acceptable)                     44.7         22.3         26.7         26.4

                 Within 72 hours or 3 days             25.0         34.9         26.2         30.8
                 (Acceptable)                                                                 

  11:            Suppose I told you a woman who is 2   93.4         92.1         90.2         91.6
                 months pregnant used Plan B. Would                                           
                 you say she used Plan B correctly or                                         
                 incorrectly? (NO)                                                            

  12:            From verbatim answer given in         92.1         95.2         91.6         93.6
                 Question 11 - Why is this                                                    
                 correct/incorrect? (Because she was                                          
                 already pregnant, it won\'t work,                                            
                 it\'s too late)                                                              

  13:            A woman used Plan B to be sure she    94.7         97.5         93.8         95.9
                 does not get any sexually transmitted                                        
                 diseases. Was this a correct use of                                          
                 Plan B? (NO)                                                                 

  14:            A woman\'s partner used a condom      78.9         91.8         92.9         90.7
                 during sex with her but the condom                                           
                 broke. The next morning, she used                                            
                 Plan B to prevent pregnancy. Was this                                        
                 a correct use of Plan B? (YES)                                               

  **15:**        **A woman had unusual vaginal         **72.4**     **77.2**     **74.7**     **75.8**
                 bleeding during the past week. She                                           
                 had unprotected sex and then she took                                        
                 Plan B to prevent pregnancy. Was this                                        
                 a correct use of Plan B? (NO)**                                              

  **16:**        **A woman with asthma had unprotected **55.3**     **64.5**     **62.7**     **62.8**
                 sex. The next day, she took Plan B to                                        
                 prevent pregnancy. Was this a correct                                        
                 use of Plan B? (YES)**                                                       

  17:            A woman has missed her period. She    86.8         90.1         89.3         89.5
                 did a home pregnancy test and it was                                         
                 positive. She then used Plan B                                               
                 because she didn\'t want to be                                               
                 pregnant. Was this a correct use of                                          
                 Plan B? (NO)                                                                 

  18:            A woman knows she is allergic to an   90.8         91.5         91.1         91.3
                 ingredient in Plan B. She used Plan B                                        
                 because she noticed that her                                                 
                 partner\'s condom broke during sex                                           
                 with her. Was this a correct use of                                          
                 Plan B? (NO)                                                                 

  19:            A woman had unprotected sex 2 days    82.9         86.2         88.9         86.7
                 ago and then used Plan B to prevent                                          
                 pregnancy. Was this a correct use of                                         
                 Plan B? (YES)                                                                

  20:            A woman had unprotected sex a week    94.7         94.6         94.2         94.5
                 ago and then used Plan B to prevent                                          
                 pregnancy. Was this a correct use of                                         
                 Plan B? (NO)                                                                 

  **21:**        **A woman is planning to have sex     **50.0**     **49.6**     **40.9**     **46.6**
                 tonight. She usually uses condoms to                                         
                 prevent pregnancy. This time she                                             
                 plans to use Plan B instead because                                          
                 her husband complains about using                                            
                 condoms. Is this a correct use of                                            
                 Plan B? (NO)**                                                               

  22:            A woman used Plan B every day instead 90.8         91.0         89.8         90.5
                 of her usual birth control pills. Was                                        
                 this a correct use of Plan B? (NO)                                           

  23:            A woman took both Plan B tablets at   93.4         96.3         96.4         96.0
                 the same time. Was this a correct use                                        
                 of Plan B? (NO)                                                              

  **24:**        **A woman stopped taking her birth    **60.5**     **67.6**     **72.4**     **68.4**
                 control pills a week ago then she had                                        
                 sex with no other birth control                                              
                 method. She then used Plan B to                                              
                 prevent pregnancy. Was this a correct                                        
                 use of Plan B? (YES)**                                                       

  **25:**        **A woman and her husband don\'t like **59.2**     **65.6**     **75.6**     **68.3**
                 using condoms and the woman doesn\'t                                         
                 want to take birth control pills.                                            
                 They decide to use Plan B as their                                           
                 main contraceptive method. Is this a                                         
                 correct use of Plan B? (NO)**                                                

  **26:**        **Will Plan B be more effective if a  **76.3**     **74.6**     **64.0**     **71.2**
                 woman takes it 1 day after                                                   
                 unprotected sex or if she takes it 2                                         
                 days after unprotected sex? (1 day)**                                        

  27:            According to the label, does Plan B   97.4         98.6         96.9         97.9
                 protect against HIV (the virus that                                          
                 causes AIDS) and other sexually                                              
                 transmitted diseases? (NO)                                                   

  28:            After a woman takes Plan B, when      84.2^\*^     89.0^\*^     89.8^\*^     88.7^\*^
                 should she expect her next period?                                           

                 ABOUT NORMAL TIME (Correct)           71.1         78.6         81.3         78.7

                 ONE WEEK LATE (Acceptable)            13.2         10.4         8.4          10.1

  29:            How many days does the label say is   85.5         91.8         92.4         91.3
                 the longest after sex a woman should                                         
                 wait before taking the first Plan B                                          
                 tablet? (3 days or 72 hours)                                                 

  30:            When should a woman take the 2nd Plan 77.6         90.1         81.8         85.8
                 B tablet?                                                                    

                 12 HOURS AFTER FIRST TAB (Correct)    55.3         75.2         64.0         69.1

                 OTHER\[12 HOURS MENTIONED\]           22.4         14.9         17.8         16.8
                 (Acceptable)                                                                 

  31:            According to the label, if a woman    81.6^\*^     84.2^\*^     77.3^\*^     81.6^\*^
                 gets severe stomach pain after using                                         
                 Plan B, what should she do?                                                  

                 MD \[no time\] (Correct)              72.4         72.7         66.2         70.4

                 MD immediately (Acceptable)           9.2          11.5         11.1         11.1

  32:            Can nausea be a side effect of Plan   100.0        99.2         98.7         99.1
                 B? (YES)                                                                     

  33:            Can trouble breathing be a side       85.5         88.2         75.1         83.4
                 effect of Plan B? (NO)                                                       

  34:            Can vomiting be a side effect of Plan 94.7         97.2         92.9         95.4
                 B? (YES)                                                                     

  35:            Can fever be a side effect of Plan B? 81.6         78.6         81.3         79.9
                 (NO)                                                                         

  36:            Are there any other possible side     96.1         93.8         93.3         93.9
                 effects that I have not mentioned?                                           
                 (YES)                                                                        

  37:            Name other side effects (LISTED ON    85.5         89.3         84.9         87.3
                 LABEL)                                                                       
  --------------------------------------------------------------------------------------------------------

**APPENDIX 3: Proposed Commercial Prototype Label**

![](media/image14.png){width="4.958333333333333in"
height="7.145833333333333in"}

![](media/image15.png){width="3.25in" height="3.0in"}

> ***Panel 1 Panel 2***

![](media/image17.png){width="3.2291666666666665in"
height="2.9791666666666665in"}

![](media/image18.png){width="3.1666666666666665in"
height="2.9583333333333335in"}

> ***Panel 4 Panel 6***
>
> ![](media/image19.png){width="3.1458333333333335in"
> height="2.96875in"}
>
> ***Panel 8 Panel 9***
>
> ![](media/image21.png){width="3.25in" height="2.9895833333333335in"}
>
> ***Panel 11 Panel 13***

**APPENDIX 4: Actual Use Study Label**

+---------+------------------------------+--------------+-------------+
| **Panel | **Item(s) Changing**         | **Label      | **Actual    |
| Numb    |                              | C            | Use Study   |
| er(s)** |                              | omprehension | to Proposed |
|         |                              | to Actual    | OTC         |
|         |                              | Use Study**  | Commercial  |
|         |                              |              | Labeling**  |
+=========+==============================+==============+=============+
| **1**   | "2 levonorgestrel tablets"   | Moved from   | No change   |
|         | and "0.75 mg each"           | upper        |             |
|         |                              | left-hand    |             |
|         |                              | corner to    |             |
|         |                              | lower        |             |
|         |                              | right-hand   |             |
|         |                              | corner       |             |
+---------+------------------------------+--------------+-------------+
| **1**   | "Emergency Contraception"    | Enlarged     | No change   |
|         |                              | font one     |             |
|         |                              | point size   |             |
+---------+------------------------------+--------------+-------------+
| **2**   | "Plan B should not be used   | Bolded       | No change   |
|         | in place of regular          |              |             |
|         | contraception."              |              |             |
+---------+------------------------------+--------------+-------------+
| **2**   | " **·** Women who have       | No change    | See Panel   |
|         | unusual vaginal bleeding."   |              | 4, dealt    |
|         |                              |              | with under  |
|         |                              |              | "warnings"  |
|         |                              |              | section     |
+---------+------------------------------+--------------+-------------+
| **2 &   | "WHAT IF I AM ALREADY        | Moved from   | No change   |
| 4**     | PREGNANT AND USE PLAN B? If  | Panel 4 to   |             |
|         | you are already pregnant     | Panel 2      |             |
|         | Plan B is unlikely to harm   |              |             |
|         | the fetus."                  |              |             |
+---------+------------------------------+--------------+-------------+
| **3**   | NO CHANGES                   |              |             |
+---------+------------------------------+--------------+-------------+
| **4**   | Percentages after listing of | No change    | Removed     |
|         | side effects                 |              |             |
+---------+------------------------------+--------------+-------------+
| **4**   | Listing of side effects      | No change    | Changed to  |
|         |                              |              | sentence    |
|         |                              |              | format,     |
|         |                              |              | instead of  |
|         |                              |              | bullets     |
+---------+------------------------------+--------------+-------------+
| **4**   | "If you have unexplained     | Not included | Addition of |
|         | vaginal bleeding, talk to    | in either    | this text   |
|         | your doctor before using     | version      | between     |
|         | Plan B."                     | under        | ectopic     |
|         |                              | warnings     | pregnancy   |
|         |                              |              | and         |
|         |                              |              | menstrual   |
|         |                              |              | changes     |
|         |                              |              | warnings    |
+---------+------------------------------+--------------+-------------+
| **4**   | ..."serious medical          | Bolded       | No change   |
|         | problem."                    |              |             |
+---------+------------------------------+--------------+-------------+
| **4 &   | "After taking Plan B you may | Moved from   | No change   |
| 8**     | have spotting or your        | Panel 8 to   |             |
|         | menstrual period might be    | Panel 4      |             |
|         | heavier (14% of users) or    |              |             |
|         | lighter (13%). Your next     |              |             |
|         | period should come at the    |              |             |
|         | normal time, or a few days   |              |             |
|         | early or late. **If your     |              |             |
|         | period is more than one week |              |             |
|         | late, you may be             |              |             |
|         | pregnant**."                 |              |             |
+---------+------------------------------+--------------+-------------+
| **5**   | NO CHANGES                   |              |             |
+---------+------------------------------+--------------+-------------+
| **6**   | "12 hours"                   | Bolded       | No change   |
+---------+------------------------------+--------------+-------------+
| **7**   | NO CHANGES                   |              |             |
+---------+------------------------------+--------------+-------------+
| **8 &   | "HOW WELL DOES PLAN B WORK?  | Moved from   | No change   |
| 9**     |                              | Panel 9 to   |             |
|         | Plan B lowers the risk of    | Panel 8      |             |
|         | pregnancy by 89% after one   |              |             |
|         | act of unprotected sex (from |              |             |
|         | about 8%, on average, down   |              |             |
|         | to about 1%), if used within |              |             |
|         | 72 hours (3 days).           |              |             |
|         |                              |              |             |
|         | Plan B works better the      |              |             |
|         | sooner you use it after      |              |             |
|         | unprotected sex."            |              |             |
+---------+------------------------------+--------------+-------------+
| **9**   | ", if used within 72 hours   | Added to     | No change   |
|         | (3 days)."                   | text at the  |             |
|         |                              | end of the   |             |
|         |                              | first        |             |
|         |                              | sentence on  |             |
|         |                              | Panel 9,     |             |
|         |                              | which was    |             |
|         |                              | moved to     |             |
|         |                              | Panel 8 (see |             |
|         |                              | line above)  |             |
+---------+------------------------------+--------------+-------------+
| **9**   | "Do not take more than 2     | Removed      | No change   |
|         | tablets in 24 hours."        |              |             |
+---------+------------------------------+--------------+-------------+
| **9 &   | "Store at room temperature.\ | Moved from   | No change   |
| 11**    | Plan B is manufactured by    | Panel 11 to  | at this     |
|         | Gedeon Richter, Ltd,         | Panel 9 and  | time        |
|         | Budapest, Hungary.           | centered     |             |
|         |                              | from top and |             |
|         | Plan B is distributed in the | bottom       |             |
|         | United States and Canada by: | margins      |             |
|         |                              |              |             |
|         | Women's Capital Corporation  |              |             |
|         |                              |              |             |
|         | 1990 M Street, NW,           |              |             |
|         | Washington, DC 20036         |              |             |
|         |                              |              |             |
|         | 800-330-1271                 |              |             |
|         | [ww                          |              |             |
|         | w.go2planb.com]{.underline}" |              |             |
+---------+------------------------------+--------------+-------------+
| **10**  | NO CHANGES                   |              |             |
+---------+------------------------------+--------------+-------------+
| **12**  | NO CHANGES TO PERMANENT      |              |             |
|         | TEXT, PERIODIC CHANGES TO    |              |             |
|         | ACTUAL LOT#, EXPIRATION      |              |             |
|         | DATE, AND/OR DATE OF         |              |             |
|         | MANUFACTURE                  |              |             |
+---------+------------------------------+--------------+-------------+
| **13**  | "contraception" under Use    | Changed to   | No change   |
|         | section                      | "birth       |             |
|         |                              | control"     |             |
+---------+------------------------------+--------------+-------------+
| **14**  | NO CHANGES                   |              |             |
+---------+------------------------------+--------------+-------------+

![](media/image23.png){width="5.260416666666667in" height="7.40625in"}

![](media/image15.png){width="3.25in" height="3.0in"}

***Panel 1 Panel 2***

![](media/image25.png){width="3.21875in" height="2.9791666666666665in"}

***Panel 4 Panel 6***

> ![](media/image19.png){width="3.1458333333333335in"
> height="2.96875in"}
>
> ***Panel 8 Panel 9***
>
> ![](media/image21.png){width="3.25in" height="2.9895833333333335in"}

![](media/image26.png){width="3.1770833333333335in"
height="2.9895833333333335in"}

> ***Panel 11 Panel 13***

**APPENDIX 5: Label Comprehension Study Label**

+----------------------------------+-----------------------------------+
| **Prescription Package Insert**  | **Proposed OTC Product Label**    |
+==================================+===================================+
| **Contraindications**            | **Who should not use Plan         |
|                                  | B/Warnings**                      |
+----------------------------------+-----------------------------------+
| Known or suspected pregnancy     | Pregnant women (Plan B cannot     |
|                                  | cause an abortion)                |
+----------------------------------+-----------------------------------+
| Hypersensitivity to any          | Women who are allergic to any     |
| component of the product         | ingredient in Plan B              |
+----------------------------------+-----------------------------------+
| Undiagnosed abnormal genital     | Rewritten in the Warnings section |
| bleeding                         | as "Do not use if you have        |
|                                  | unusual vaginal bleeding"         |
+----------------------------------+-----------------------------------+
| **Warnings**                     |                                   |
+----------------------------------+-----------------------------------+
| Plan B is not recommended for    | Plan B is not recommended for     |
| routine use as a contraceptive.  | regular contraception.            |
+----------------------------------+-----------------------------------+
| Plan B is not effective in       | Do not use if you are already     |
| terminating an existing          | pregnant (because it will not     |
| pregnancy.                       | work)                             |
+----------------------------------+-----------------------------------+
| **Effects on Menses**            | After taking Plan B you may have  |
|                                  | spotting or your menstrual period |
| Menstrual bleeding patterns are  | might be heavier (14% of users)   |
| often irregular among women      | or lighter (13%). Your next       |
| using progestin-only oral        | period should come at the normal  |
| contraceptives and in clinical   | time, or a few days early or      |
| studies of levonorgestrel for    | late. **If your period is more    |
| postcoital and emergency         | than one week late, you may be    |
| contraceptive use. Some women    | pregnant.**                       |
| may experience spotting a few    |                                   |
| days after taking Plan B. At the |                                   |
| time of expected menses,         |                                   |
| approximately 75% of women using |                                   |
| Plan B had vaginal bleeding      |                                   |
| similar to their normal menses,  |                                   |
| 12-13% bled more than usual, and |                                   |
| 12% bled less than usual. The    |                                   |
| majority of women (87%) had      |                                   |
| their next menstrual period at   |                                   |
| the expected time or within ± 7  |                                   |
| days, while 13% had a delay of   |                                   |
| more than 7 days beyond the      |                                   |
| anticipated onset of menses. If  |                                   |
| there is a delay in the onset of |                                   |
| menses beyond 1 week, the        |                                   |
| possibility of pregnancy should  |                                   |
| be considered.                   |                                   |
+----------------------------------+-----------------------------------+
| **Ectopic Pregnancy**            | **See a doctor right away if you  |
|                                  | have severe stomach pain,** since |
| Ectopic pregnancies account for  | this can be a warning sign of     |
| approximately 2% of reported     | tubal (ectopic) pregnancy -- **a  |
| pregnancies (19.7 per 1000       | serious medical problem**.        |
| reported pregnancies). Up to 10% |                                   |
| of pregnancies reported in       |                                   |
| clinical studies of routine use  |                                   |
| of progestin-only contraceptives |                                   |
| are ectopic. A history of        |                                   |
| ectopic pregnancy need not be    |                                   |
| considered a contraindication to |                                   |
| use of this emergency            |                                   |
| contraceptive method. Health     |                                   |
| providers, however, should be    |                                   |
| alert to the possibility of an   |                                   |
| ectopic pregnancy in women who   |                                   |
| become pregnant or complain of   |                                   |
| lower abdominal pain after       |                                   |
| taking\                          |                                   |
| Plan B.                          |                                   |
+----------------------------------+-----------------------------------+

![](media/image27.png){width="5.1875in" height="7.3125in"}

![](media/image28.png){width="3.2395833333333335in"
height="2.9895833333333335in"}

***Panel 1 Panel 2***

![](media/image18.png){width="3.1666666666666665in"
height="2.9583333333333335in"}

> ***Panel 4 Panel 6***

![](media/image31.png){width="3.1770833333333335in"
height="2.9791666666666665in"}

> ![](media/image32.png){width="3.1770833333333335in"
> height="2.9791666666666665in"}
>
> ***Panel 8 Panel 9***
>
> ![](media/image33.png){width="3.2083333333333335in"
> height="2.9791666666666665in"}
>
> ***Panel 11 Panel 13***

APPENDIX 6: Categorization of Verbatim Terms for Label Comprehension
Study Question #7

**Question 7: Without looking at the label, tell me what Plan B is used
for.**

**1=CONTRACEPTION AFTER SEX (correct and acceptable)**

> a day after contraceptive
>
> a emergencey contraception
>
> a emergency contraception
>
> a emergency contraceptive
>
> a emergency contracteption
>
> a morning after pill
>
> a morning after tablet or pill
>
> a morning after type product
>
> abortion
>
> abortion drug
>
> abortion pill
>
> after have unprotected sex take it under 72 hours if you don\'t want
> to get preg
>
> after having sex if you are afraid of\...didn\'t use contraception
>
> after sex not to get pregnant
>
> after unprotected sex a contraceptive
>
> after unprotected sex it\'s a drug used to protect against pregnancy
>
> after unprotected sex to avoid pregnancy
>
> after unprotected sex to prevent from pregnancy
>
> after you have unprotected sex and you don\'t want to get pregnant
> take the pill
>
> after you have unprotected sex you take it to prevent pregnancy
>
> an abortion type of thing if you think you are pregnant
>
> an abortion type thing for the day after
>
> an emergency contraception
>
> an emergency contraceptive
>
> an emergency contraceptive for birth control after sex
>
> an emergency contraceptive morning after pill
>
> an emergency pill to use if you think you\'re pregnant
>
> as a form of emergency birth control
>
> as emergency birth control i believe
>
> birth control after unprotected sex
>
> birth control like a morning after pill
>
> birth control to use the next day
>
> contracepted after unprotect sex
>
> contraception after having sex
>
> contraception after unprotected sex
>
> contraception reduces a pregnant chance after unprotected sex
>
> contraceptive emergency
>
> contraceptive if you didn\'t use one or if it broke
>
> day after intercourse to make sure you are not pregnant
>
> day after pill
>
> day after pill so you dont get pregnant
>
> day after pill to get rid of pregnancy 72 hours after you have
> unprotected sex
>
> emer birth control
>
> emerg birth control
>
> emergency after pill
>
> emergency after sex pill
>
> emergency backup pill for not getting pregnant
>
> emergency birth control
>
> emergency birth control pill
>
> emergency birth control pills
>
> emergency compensation
>
> emergency conception
>
> emergency con-something
>
> emergency contraceptave
>
> emergency contraception
>
> emergency contraception (pregnacy)
>
> emergency contraception if you got raped condem broke forgot birth
> control pill
>
> emergency contraception incase you get pregnant
>
> emergency contraception morning after pill
>
> emergency contraception or morning after pill
>
> emergency contraception pill
>
> emergency contraception to help stop pregnancy
>
> emergency contraception within 72 hours if not already pregnant
>
> emergency contraception within 72 hours of having sex
>
> emergency contraceptive
>
> emergency contraceptive like the morning after pill
>
> emergency contraceptive use up to 3 days after unprotected sex or if
> cont fail
>
> emergency contraceptives
>
> emergency contreceptive
>
> emergency contriceptive the morning after pill
>
> emergency pills
>
> emergency pills to keep you from being pregnant
>
> emergency prevention of pregnancy
>
> for emergency contraception
>
> for if you have sex and you didn\'t take birth control or use a condom
>
> for unprotected sex so you won\'t come out pregnant
>
> for unprotected sex to prevent pregnancy
>
> had unprotected sex would take it within 72 to prevent pregnancy
>
> helps prevent pregnancy if your contraceptive fails you
>
> if you have sex without a condom or any other birth control
>
> if you have unprotected sex and don\'t want to be pregnant
>
> if you have unprotected sex its supposed to kill the sperm
>
> if you use it after you have unprotected sex you won\'t get pregnant
>
> if your contreception failed or if one was not used
>
> in case you had unprotected sex it stops pregnancy
>
> it has 2 emergency contraceptive birth control pills
>
> it is a emergencey contraception
>
> it is a emergency contraception
>
> it is a emergency contraception after having sex for not getting
> pregnant
>
> it is a emergency pill and probably take it every day for birth
> control
>
> it is a pill you take after you have unprotected sex
>
> it is a type of contraception to be used in an emergency situation
>
> it is a type of emergency contraception
>
> it is an emergency contraception
>
> it is emergency contraception
>
> it kills sperm right after sex
>
> it looks like its used for emergency contraception
>
> its a birth control pill for emergencies a day after pill
>
> its a morning after pill
>
> its an emergency birth control pill
>
> its an emergency contraceptive
>
> its emergency contraception to be taken 72 hours after unprotected sex
>
> its emergency contraceptives
>
> its for contraception after you have sex
>
> it\'s like a after pill in case your contraception won\'t work
>
> it\'s like a day after pill
>
> its like a morning after pill
>
> it\'s says it\'s not or too avoid pregnancy after intercourse
>
> it\'s the morning after pill
>
> its the morning after pill, reduce your chances of getting pregnant
> after
>
> its used to prevent pregnancy after unprotected sex
>
> it\'s used to stop pregnancy after you have had sex
>
> like a morning after pill or something
>
> like the day after pill you take after having sex so you won\'t get
> pregnant
>
> like the morning after pill kinda
>
> morning after pill
>
> morning after pill after unprotected sex
>
> morning after pill have sex and don\'t use protection can take it
> within 72 hrs
>
> morning after unprotected sex
>
> not to get pregnant after unprotected sex
>
> oral emergency contreceptive
>
> plan b is something you take after sex to keep you from getting
> pregnant
>
> preven u from getting pregnant so if you have unprotected sex you get
> a chance
>
> prevent pregnancy after unprotected sex
>
> preventing pregnancy after unprotected sex
>
> preventing pregnancy after unprotected sex or failed contraceptives
>
> prevents you from getting pregnant after having sex
>
> reduced the chance of pregnancy for unprotected sex
>
> reduces chance of pregnancy after unplanned sex
>
> so that if you have unprotected sex you will not get pregnant
>
> so you won\'t be pregnant after unprotected sex
>
> something similar to the morning after pill i think but not sure
>
> something you take for you not to get pregnant after unprotected sex
>
> stops you from being knocked up if the rubber breaks
>
> take it after unprotected sex to stop you from getting pregnant
>
> take it after you have unprotected sex
>
> that morning after drug for unprotected sex
>
> the after morning pill
>
> the day after pill
>
> the morning after pill
>
> the morning after pill i think
>
> to keep you from being pregnant when you don\'t use protection or it
> fails on u
>
> to kill the firtilized egg
>
> to prevent pregnancy after having unprotected sex
>
> to prevent pregnancy after unprotected sex
>
> to prevent pregnancy contraception in case of an emerge
>
> to prevent pregnancy if there is a chance you may be pregnant
>
> to reduce chance of pregnancy if contraceptive wasn\'t used during sex
>
> to take care pregnancy after unprotected sex
>
> unprotected sex it reduces the risk of pregnancy
>
> unprotected to reduce pregnancy after unprotected sex
>
> well the outside said emergency contraceptive
>
> when having unprotected sex so you don\'t get pregnant
>
> when your contraception fails it\'s a back up plan
>
> you won\'t get pregnant day after program

**2=contraception (acceptable)**

> \"cuts down the chance of getting pregnant\"
>
> \"it\'s birth control\"
>
> a birth control pill
>
> a conceptative
>
> a contraceptive
>
> a contraceptive birth control
>
> a form of birth control
>
> a method of birth control
>
> a pill not to get pregnant
>
> a pill you take when you dont want to get pregnant
>
> a pregnancy contraception a form of birth control
>
> a type of birth control
>
> a type of birth control pill
>
> a type of contraceptive
>
> alt. contraceptive
>
> alternative contraceptive
>
> an form of contreceptive
>
> avoid pregnancy
>
> back up birth control
>
> back up contraception
>
> back up contraception pills
>
> back up pills
>
> back up plan for when your other birth control fails
>
> backup birth control
>
> birth contraceptive
>
> birth control
>
> birth control contraceptive
>
> birth control i guess
>
> birth control or something
>
> birth control pill
>
> birth control pills
>
> birth control/contraceptive
>
> birth controll
>
> birthcontrol
>
> conceptrative
>
> constraception
>
> conterception
>
> contraception
>
> contraception it says
>
> contraception to stop pregnancy
>
> contraceptive
>
> contraceptive birth control
>
> contraceptive pills prevent pregnancy
>
> contraceptives
>
> contraceptives just in case
>
> contreception to prevent unwanted pregnancy
>
> contreceptive
>
> for contraceptive
>
> for contrecepting
>
> for pregnancy to prevent it
>
> for the prevention of pregnancy
>
> girls who don\'t want to be pregnant
>
> helps prevent unplanned pregnancy from occuring
>
> helps you so you don\'t get pregnant
>
> I guess, I don\'t know, birth control, protection
>
> if case you are worried in getting pregnant
>
> if you don\'t want to be pregnant
>
> if your not pregnant it\'s to keep from getting pregnant
>
> i\'m guessing birth control
>
> i\'m not quite sure maybe pills to prevent conception
>
> i\'m not sure but probably preventing pregnancy
>
> i\'m not sure some kind of pregnacy preventer maybe
>
> it is a contreaceptive
>
> it is a pill you take so you wont become pregnant
>
> it is to used to keep you from getting pregnant
>
> it is used to help prevent you from having a baby
>
> it is used to prevent pregnancy
>
> it is used to prevent pregnency
>
> it is used to prevent you from having a child
>
> it is used to whatchmacallit to prevent getting pregnant
>
> it may be for some kind of birth control
>
> its a contraceptive
>
> it\'s a contraceptive
>
> it\'s a contraceptive to keep you from getting pregnant
>
> it\'s a pill that is used for not getting pregnant
>
> it\'s a pill used for not getting pregnant
>
> it\'s a type of birth control
>
> it\'s for a protection for sex a contraception
>
> its for birth control
>
> its for to not get pregnant its like for birth control
>
> it\'s kinda a form of birth control but not really it prevents
> pregnancy
>
> it\'s probably to prevent pregnancy
>
> it\'s the \"i don\'t want to be pregnant\" pill
>
> it\'s used for preventing pregnancy
>
> keeps you from getting pregnant
>
> like a birth control pill
>
> like the pill
>
> not to be pregnant
>
> not to get pregnant
>
> not to get pregnant and if you are pregnant don\'t take it
>
> plan b is a type of birth control
>
> plan b is for preventing pregnancy
>
> plan b is used for birth control pills
>
> pregnancy control pill
>
> pregnancy pil so you won\'t get pregnant
>
> pregnancy prevention
>
> pregnancy prevention pill
>
> pregnancy to prevent pregnancy
>
> prevent from getting pregnant
>
> prevent of pregnancy
>
> prevent pregency
>
> prevent pregnancies
>
> prevent pregnancy
>
> prevent you from getting pregnant
>
> preventing pregnancy
>
> preventing unwated conception
>
> prevention of pregnancy
>
> prevents unwanted pregnancy
>
> protection prevent from getting pregnant
>
> reduce chance of pregnancy
>
> reduce the chance of getting pregnant
>
> reduces the chance of getting pregnant
>
> so you can\'t get pregnant
>
> so you don\'t get pregnant
>
> so you wont get pregnant
>
> so you won\'t get pregnant
>
> some type of pregnancy pill-birth control
>
> something to prevent pregnancy
>
> stop pregnancy
>
> stops you from being pregnant
>
> there used for birth control
>
> to avoid pregnancy
>
> to help prevent pregnancy
>
> to help you not get pregnant
>
> to keep you from being pregnant
>
> to keep you from getting pregnant
>
> to make sure you dont get pregnant
>
> to minimize the chances of getting pregnant
>
> to not get pregnant
>
> to prevent conception
>
> to prevent not getting pregnant
>
> to prevent pregnancy
>
> to prevent use from pregnancy i guess
>
> to prevent you from getting pregnant
>
> to protect you from having kids
>
> to reduce risk of pregnancy
>
> to reduce the chance of getting pregnant
>
> to reduce the chance of pregnacy
>
> to stop pregnancy
>
> type of birth control
>
> type of contreceptive pill
>
> well i would have to say in place of a condom like the morning after
> pill

**3=emergency, sex not mentioned (incorrect and not acceptable)**

> emergencies
>
> emergency medication
>
> emergency pregnancy pill
>
> emergency situations
>
> emergenies
>
> for emergency pain, sex

**4=STI/HIV (incorrect and not acceptable)**

> for hiv (w) pregnancy (w) aids (w)it
>
> hiv
>
> hiv-aids
>
> if you have HIV
>
> prevent against stds
>
> protect against hiv
>
> protect hiv
>
> sexually transmitted diseases

**5=after sex, purpose unspecified**

> after having unprotected sex
>
> after sex pills
>
> after sex the emergency thing
>
> after unprotected sex
>
> after you already had sex and you kind of screwed up
>
> after you have sex you can use that afterward
>
> for after you\'ve had unprotected sex
>
> for unprotected sex
>
> for when you have unprotected sex
>
> if you have unprotected sex
>
> in case you had unprotected sex or a condom broke or something like
> that
>
> in case you have unprotected sex
>
> it\'s for if you\'ve had unprotected sex
>
> they are tablets for if you didn\'t have protected sex
>
> to protect yourself from unprotected sex
>
> to use after unproted sex
>
> unprotected sex
>
> used for unprotected sex
>
> **6=other**
>
> a pregnancey test or something
>
> conception
>
> for no mistaking regular things constipation
>
> for pregnancy
>
> for protection of sex
>
> for sexually active stuff
>
> for when you have headaches
>
> headaches?
>
> i think pregnancy
>
> it looks like allergy pills
>
> medication
>
> miscarry babies not miscarry but get it out
>
> nausea pain
>
> pains
>
> pregnancy
>
> probably having sex
>
> protection for sex
>
> second choice
>
> sex
>
> something having to do with being pregnant
>
> something to do with a cold or allergies
>
> take for percautions
>
> to find out if your pregnant if you are don\'t use it
>
> to get rid of a mistake
>
> unwanted pregnancy

**9=don\'t know/refused**

> don\'t know or refused
>
> i did not look at that
>
> i don\'t think i looked that closely
>
> i have no idea
>
> i have no idea i forgot already
>
> i wouldn\'t know that
>
> i\'m not sure
>
> maybe like a\...a kind of birth control or to kill an infection I\'m
> not sure
>
> not sure

**APPENDIX 7: PROPOSED PATIENT PACKAGE INSERT**

What you should know about Plan B^®^

**Plan B^®^ is a backup method of birth control.**

Plan B^®^ is *emergency contraception*, a backup method of birth
control. Plan B^®^ can reduce your risk of pregnancy if you have
unprotected sex (if your regular birth control method fails or if you
have sex without birth control).

Plan B^®^ contains a concentrated dose of *levonorgestrel*, a synthetic
hormone used in birth control pills for over 35 years.

Because Plan B^®^ prevents pregnancy before if begins, it is not the
same as abortion.

You can use Plan B^®^ if you had unprotected sex one or more times in
the last three days (72 hours), and you don't want to become pregnant.

Plan B^®^ is not as effective as using a regular birth control method
correctly and consistently. It can be used as a backup method if:

-   Your regular birth control failed (your partner's condom broke or
    slipped)

-   You made a mistake with your regular method (you missed several
    birth control pills)

-   You did not use any birth control method

**Plan B^®^ works better the sooner you use it.**

Your only have a few days to prevent pregnancy after unprotected sex.
Plan B^®^ works better the sooner you use it. Take the first Plan B^®^
tablet **as soon as possible** within three days (72 hours) of
unprotected sex. Take the second tablet 12 hours later.

Plan B^®^ can reduce the risk of pregnancy to about 1 percent, if you
use it within the first three days of a single act of unprotected sex.
Your risk of pregnancy ranges from 0 to 35 percent, depending on the day
of your menstrual cycle.

**Plan B^®^ works like other birth control pills.**

Plan B^®^ can prevent pregnancy by stopping the release of an egg from
the ovary (*ovulation*), or it may prevent the union of sperm and egg
(*fertilization*). You are at most risk of pregnancy just before
ovulation and on the day of ovulation.

If fertilization does occur, Plan B^®^ may prevent a fertilized egg from
attaching to the womb (*implantation*). Plan B^®^ will not work after
implantation of a fertilized egg.

Plan B^®^ is not the same as the early abortion pill, Mifeprez^®^
(RU486). Plan B^®^ cannot disrupt an established pregnancy.

**Some women experience short-term side effects?**

Plan B^®^ has no serious or lasting medical side effects. Some women
will experience non-serious side effects, such as nausea, stomach pain,
headache, dizziness, or breast tenderness. These are similar to the side
effects of regular birth control pills. Some women have menstrual
changes such as spotting or bleeding before their next period. Some
women may have a heavier or lighter next period, or a period that is
early or late. If your period is more than a week late, you should get a
pregnancy test.

**Plan B^®^ will not harm an established pregnancy?**

Plan B^®^ should not have any effect on an established pregnancy. If you
take it accidentally after you are already pregnant, or if it does not
work, it is not likely to cause any harm to you or your pregnancy.
Studies of women who took birth control pills by mistake after they were
already pregnant showed no increased risk of birth defect.

**Warnings**

If you become pregnant after using Plan B^®^, and you have sever stomach
pain, contact a doctor immediately. This may be a sign of an ectopic
pregnancy (a pregnancy growing in your fallopian tube).

Keep this and all drugs out of the reach of children. In case of
accidental ingestion, call a Poison Control Center, emergency medical
facility, or a doctor immediately.

Each Plan B^®^ package is sealed in plastic wrap. If the wrap is missing
or torn, return the package to your pharmacy.

Questions or Comments

Call 1-800-330-1271 or visit www.go2planb.com

**Choosing a Regular Method of Birth Control**

Plan B^®^ is a safe and effective **emergency contraceptive** for use
when you need a backup method of birth control.

***Plan B^®^ is not a substitute for regular contraception.*** Using a
regular contraceptive correctly and consistently would be more effective
and may be less expensive. Plan B^®^ does not protect you against
sexually transmitted infections, including HIV/AIDS.

If you are sexually active but you are not using a regular birth control
method, or if you are having trouble using your method, you should talk
with a healthcare professional. Women who are sexually active and use no
birth control method for a year have an 85% risk of becoming pregnant.

Listed below are birth control choices that you may want to discuss with
your healthcare provider. In some cases, Plan B^®^ may be a good backup
for the method you choose.

**Abstinence**

Sexual abstinence is the most effective way to avoid both unintended
pregnancy and sexually transmitted infections, including HIV/AIDS.
Sexual abstinence requires commitment and self-control on the part of
both partners in a relationship. For women practicing abstinence, Plan
B^®^ can be useful back-up method, if unplanned sex does occur.

**Birth Control Pill**

Most birth control pills contain *progestin* and *estrogen*. These
active ingredients are synthetic versions of naturally occurring female
hormones. *Progestin*-only pills are available for women who should not
take estrogen because of cardiovascular or other risk factors. All birth
control pills currently require a prescription. Birth control pills are
highly effective if they are used correctly and consistently. Because
women sometimes forget to take their pills, the typical pregnancy rate
in the first year of use is about 8%. Advantages of the pill include
more regular periods, less menstrual bleeding, decreased menstrual
cramps, and a reduction in the risk of endometrial and ovarian cancer.
Side effects may include nausea, breast tenderness, and headaches, but
these symptoms often decrease after the first few months of pill use.
Birth control pills provide no protection against sexually transmitted
infections or HIV/AIDS. Plan B^®^ can be used as a backup contraceptive
if you miss two or more pills in a row or if you start a new cycle of
pills late. You can start taking your pills again as soon as you finish
your Plan B^®^.

**Condom**

Many different types of condoms for men are available in pharmacies
without a prescription. Condoms can prevent pregnancy and can also
reduce the risk of getting HIV/AIDS or other sexually transmitted
infections. To be most effective, condoms must be used correctly and
consistently. Condoms break or slip 3% to 5% of the time. As a result of
condom accidents and inconsistent use, the typical risk of pregnancy is
about 15% in the first year of use. A polyurethane female condom, worn
inside the vagina, is also available without a prescription. The female
condom can prevent both pregnancy and sexually transmitted infections,
including HIV/AIDS. The risk of pregnancy is about 21% in the first year
of typical use. Couples depending on male or female condoms for birth
control may find it useful to keep Plan B^®^ in the nightstand in case
of a condom accident or if unprotected sex occurs.

**Diaphragm, Cervical Cap and Sponge (Female Barrier Methods)**

Female barrier methods prevent pregnancy by stopping sperm from reaching
the uterus. The diaphragm and cap are used with a spermicide; the sponge
contains a spermicide. (See "Spermicides" below). These methods do not
require a prescription. Plan B^®^ can be a useful backup method when a
diaphragm or cervical cap moves out of place during sex, or if
unprotected sex occurs.

**Implant (Contraceptive Implant)**

New contraceptive implants, lasting two to three years, are available in
Europe and should be available soon in the United States. Implants allow
the steady release of low doses of *progestin*, a synthetic version of a
naturally occurring female hormone. Implants are highly effective and
convenient for women who want long-term contraception. Pregnancy rates
are less than 0.5% in the first year if typical use. Like other
*progestin*-only methods, implants can cause irregular menstrual
bleeding, including spotting and less frequent periods. Implants must be
inserted under the skin and surgically removed by a healthcare
professional.

**Injectable Contraceptive**

Injectable contraceptives (birth control shots) are highly effective and
more convenient for some women than daily pills. Only 3% of users
typically get pregnant in the first year of use. The shots generally
work in the same way as birth control pills. There are two types
available in the United States. Both require a prescription. Plan B^®^
can be used as a backup if you are late getting your contraceptive
injection.

**Intrauterine Device (IUD)**

IUDs are contraceptive devices that are inserted into the uterus. They
can work for ten years or more, but they must be inserted and removed by
a healthcare professional. IUDs provide no protection against sexually
transmitted infections, including HIV/AIDS. They are not recommended for
women who may be exposed to sexually transmitted infections, such as
women with more than one sexual partner. Plan B^®^ can be a useful
backup method on those rare occasions when an IUD becomes dislodged or
expelled.

**Natural Family Planning (Periodic Sexual Abstinence)**

Natural family planning (sometimes called "fertility awareness" or
"periodic sexual abstinence") generally involves abstaining from vaginal
sex during fertile days of the menstrual cycle. There are a number of
different methods. Most couples need some months of training in order to
use the method effectively. Typical pregnancy rates in the first year of
use are about 25%. Natural family planning methods provide no protection
against sexually transmitted infections, including HIV/AIDS. Plan B^®^
can be used as a backup for natural family planning if, for example, a
women realizes after sex that she has miscalculated the fertile period.

**Patch (Transdermal Patch)**

One of the newest methods of birth control is a patch that releases low
doses of *estrogen* and *progestin*, synthetic versions of naturally
occurring female hormones. Women use one patch per week for three weeks,
followed by a break of one week. The patch is worn on the abdomen,
buttocks, upper arm or upper torso (except on the breasts). The patch
prevents pregnancy in the same way birth control pills do, but may be
more convenient for some women. The patch has many of the same
advantages and disadvantages as the birth control pill. Side effects and
pregnancy rates in the first year are expected to be similar to that of
the pill. The patch requires a prescription. Plan B^®^ can be a useful
backup method if you apply a new patch late.

**Spermicide**

Spermicides are often used with female barrier methods, such as
diaphragms, but may also be used alone. Spermicides work by attacking
sperm. They are available without a prescription, but must be used each
time you have sex. Used alone, they have a typical first year pregnancy
rate of 29%. Their main advantage is that they are widely available in
pharmacies and can be used without a male partner's cooperation. They do
not protect against HIV/AIDS. For women who rely solely on spermicides
alone or with a barrier method, Plan B^®^ may be a useful backup if
unprotected sex occurs.

**Vaginal Ring**

Another new method of birth control is the vaginal ring. The ring
releases low levels of estrogen and progestin, synthetic versions of
naturally occurring female hormones. The ring is worn inside the vagina
continuously for three weeks, followed by a break for one week. It does
not need to be removed during sexual intercourse. It works the same way
as birth control pills and has many of the same advantages and
disadvantages. Side effects and failure rates are expected to be
similar. The ring requires a prescription. Plan B^®^ can be a useful
backup method if you insert a new vaginal ring late.

**Voluntary Sterilization**

Contraceptive sterilization for women involves blocking off the
fallopian tubes by a variety of means to prevent the passage of eggs and
sperm. Male sterilization blocks the passage of sperm. Sterilization is
highly effective, with a typical first year pregnancy rate of 0.5% for
female sterilization and 0.15% for male sterilization. Advantages of
female sterilization may include decreased risk of ovarian cancer.
Disadvantages may include risk of ectopic pregnancy in the event of
failure. Neither male nor female sterilization provide any protection
against sexually transmitted infections, including HIV/AIDS. Most
methods of sterilization involve minor surgery. Sterilization is a
permanent method and should be considered only by women and men who are
certain they want no more children.

**Sources:**

1\. Hatcher RA, Nelson MA, Zieman M et al. A Pocket Guide to Managing
Contraception. Tiger, Georgia: Bridging the Gap Foundation, 2002.

http://www.managingcontraception.com/images/pds/managing.pdf

2\. Trussell J. Contraceptive failure. In Hatcher RA, Trussell J,
Stewart F, et al. Contraceptive Technology: Eighteenth Revided Edition.
New York NY: Ardent Media, 2004.

> **APPENDIX 8: Label Comprehension Study Data Transcription Card**

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[^1]: *Albania, Belgium, Benin, Cameroon, Congo, Denmark, Dominican
    Republic, Finland, France, French Polynesia, Gabon, Guinea-Conakry,
    India, Ivory Coast, Madagascar, Mali, Mauritius, Namibia, New
    Zealand, Niger, Portugal, Senegal, South Africa, Sri Lanka,
    Switzerland, Togo, (Trinidad & Tobago), Tunisia, Uganda, United
    Kingdom*

[^2]: Eligibility requirements included: emergency contraception was
    requested for personal use, no previous participation in the Plan B
    OTC Label Comprehension Study, ability to read English (according to
    women's own judgment), no previous screening for contraindications
    to emergency contraceptive pills by clinic or pharmacy staff before
    arriving at the clinic or pharmacy, willingness to complete
    questionnaires and be contacted or return to the study site in 1 and
    4 weeks for follow-up, and indication that the woman wanted the
    study product after reading the text on the outside of the study
    package label.

[^3]: The subjects were reimbursed a standard amount for their time in
    completing the study. However, subjects were not told about the
    reimbursement until after they had reviewed the study package and
    indicated their decision as to whether they should received study
    drug.

[^4]: It should be noted when looking at this table that the percentages
    for the contraindicated and incorrect use of the product were for
    the total of those reported; they were not separated into
    product-related or nonproduct-related. In addition, the total number
    of women who used the product in a contraindicated fashion was only
    7, so the percentages that are given have wide margins of error.