This briefing document summarizes information in support of the proposed R_x-to-over-the-counter (OTC) switch for the marketed emergency contraceptive, Plan B^Ò and describes the proposed CARE^SM (Convenient Access Responsible Education) 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.

1.2 Executive Summary

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).

1.2.2 Emergency Contraception

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.

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).

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 Bwas 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.

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.

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.

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).

1.2.2.7 Potential Impact of Expanded Access to Emergency Contraception

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.

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 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).

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.

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.

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, Ectopic pregnancy	Benign ovarian germ cell teratoma, Ectopic pregnancy	9/11/2002
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, spontaneous abortion	Unintended pregnancy, abortion	3/6/2003
Ectopic pregnancy	Ectopic pregnancy	3/6/2003
Ectopic pregnancy	Ectopic pregnancy	3/18/2003
Fetus detached from uterine wall	Abruptio placentae	4/2/2003
Unintended pregnancy	Unintened pregnancy	4/16/2003
Ectopic pregnancy	Ectopic pregnancy	4/16/2003
Unintended pregnancy, hospitalization after spot bleeding, induced abortion	Unintended pregnancy, antepartum hemorrhage, induced abortion	5/6/2003
Ruptured tubal pregnancy	Ruptured tubal pregnancy	5/21/2003
Right ruptured tubal pregnancy	Ruptured tubal pregnancy, vaginal bleeding	5/21/2003
Possibility of a right-sided ectopic pregnancy	Abdominal pain, nausea, right ectopic pregnancy	5/21/2003
Unintended pregnancy, miscarriage	Unintended pregnancy, missed spontaneous abortion	5/21/2003
Ectopic pregnancy, ovarian cystectomy	Ectopic pregnancy	7/11/2003
Unintended pregnancy	Unintended pregnancy	5/21/2003
Unintended pregnancy, premature rupture of membrane	Unintended pregnancy, caesarean section	5/28/2003
Ectopic pregnancy	Ectopic pregnancy, laparotomy, salpingectomy	5/28/2003
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).

Table 2: Summary of Adverse Events by Body System

Preferred Term	Non-serious Events		15-Day Alert Events
Preferred Term	Number of Reported Events	Percentage of Total Events	15-Day Alert 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 Events		15-Day Alert Events
Preferred Term	Number of Reported Events	Percentage of Total Events	15-Day Alert 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.

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.

1.2.4 Plan B: R_x-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 R_x-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 R_x-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 R_x-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 (Convenient Availability Responsible Education, 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.

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, th