**Medical Officer Safety Review**

**I. Background:**

Plan B was approved for use as an emergency contraceptive on July 28,
1999 and launched 8-23-99. The product contains only a progestin,
levonorgestrel, in two single-dose tablets (each 0.75 mg). This differs
from the first approved emergency contraception pills (ECPs) Preven ™
which contains four tablets, each with 0.25 mg levonorgestrel and 0.05
mg ethinyl estradiol. The approved regimen for Plan B is two doses taken
12 hours apart. It should be started within 72 hours of unprotected
intercourse.

The sponsor has submitted an application for the product to go OTC
(over-the-counter). There are several questions that must be answered in
order to determine whether a product is suitable for a prescription to
OTC switch. These questions include, from a safety perspective:

1.  Does the product have an acceptable margin of safety as based on
    prior prescription marketing experience?

2.  Does the product have a low misuse and abuse potential?

3.  Do the benefits from the OTC switch outweigh the risks?

4.  Is the self-treatment product safe and effective during consumer
    use?

**II. Safety Data:**

**A. Original NDA data:**

The applicant in the original Plan B NDA presented clinical trial safety
results from four general trial categories. These were:

1.  Single Dose and Multiple Dose Clinical Pharmacology Studies

    2\. Two World Health Organization (WHO/HRP) sponsored comparative
    studies that were the main studies supporting efficacy and safety.
    The trials compared levonorgestrel (0.75 mg) to the Yuzpe regimen
    \[levonorgestrel + ethinyl estradiol\] for emergency contraception.

-   WHO/HRP 1998 -- Study 92908: **the pivotal study for the NDA, N =
    1,955**

-   Ho and Kwan 1993 -- WHO/HRP Study 81107: **supportive study for the
    NDA, N = 834**

    3\. Three WHO/HRP‑sponsored trials of routine postcoital
    contraception with the levonorgestrel 0.75 mg formulation
    manufactured by Gedeon Richter

-   WHO/HRP 1987 -- Study 82906

-   WHO/HRP 1993 -- Study 87908

-   He 1991 -- WHO/HRP Study 84902

4.  Fifteen small studies of oral levonorgestrel for routine or
    occasional postcoital contraceptive use, using a variety of
    regimens, doses, and formulations.\*

\*See Table 4 at the end of this review for a listing of several
levonorgestrel studies for postcoital contraception.

Levonorgestrel, taken for postcoital contraception, is well tolerated
and safe as shown by the extensive safety data from more than 15,000
women in the above studies using various doses of levonorgestrel for
emergency contraception, occasional postcoital contraception, or routine
postcoital contraception. The data in the NDA represented the bulk of
both literature and unpublished study reports found as a result of an
extensive literature search. The search did not uncover any serious
adverse events, and the side effects reported were consistent across the
studies. No serious adverse events were reported during the 1999 NDA
review from three ongoing studies of levonorgestrel or from introductory
trials of Postinor-2 (levonorgestrel) in three countries. There were no
thromboembolic events or ectopic pregnancies in these trials. One
significant finding was that levonorgestrel was superior to the Yuzpe
regimen \[levonorgestrel + ethinyl estradiol\] for the side effects of
nausea and vomiting, and Plan B was thus labeled.

**B. Postmarketing (PM) Safety Data and Levonorgestrel ECP
Distribution:**

**1. Distribution/Use:** Since the product launch in August 1999, the
applicant estimates that 2.4 million women in the United States have
used Plan B. From 7-28-02 to 7-27-03, 1,458,536 units of Plan B were
sold; an estimated 80% were used by \~1.2 million women in the USA.
Marketing began in Canada on 6-23-00; in the most recent reported year,
the applicant estimates that 72,000 women used Plan B in Canada. In the
UK, the applicant estimates that 2.1 million women have taken Levonelle
(identical to Plan B) since February 2000. Patient exposure in France is
estimated to be 1.8 million uses. Levonorgestrel for emergency
contraception is available in 101 countries and is available without a
prescription at the pharmacy in 33 of these 101 countries.

**2. Applicant PM Data:** The applicant compiled postmarketing data from
a number of USA and global sources, including key European countries,
Canada, and the WHO Drug Monitoring Program, to provide an assessment of
the PM safety profile of levonorgestrel 0.75 mg tablets up to January
2003. There have been no reported deaths; most of the adverse events
(AEs) attributed to the drug are mild and short-term. The most common
AEs are nausea, abdominal pain, fatigue, headache, and changes in
menstrual bleeding. In the 3-year period covered by the applicant\'s
required Periodic Safety Updates[^1] to the FDA and in their subsequent
annual report, there have been 328 reported AEs. Pregnancy (123/328) and
metrorrhagia (heavy bleeding; 64/328) are the two events most frequently
reported. All of these events are consistent with the approved Plan B
label and the proposed Plan B OTC labeling.

**3. FDA PM Data:** The Agency\'s Office of Drug Safety (ODS) was
consulted and focused on the FDA Adverse Event Reporting System (AERS)
and United Kingdom (UK) databases for adverse events reported up to
10-9-03.[^2] There were no reports of death in women using postcoital
levonorgestrel in either the AERS or the UK\'s database. The search
identified 116 unduplicated cases; most of the reports involved
non-serious expected (labeled) events. The most common non-serious
events were: vaginal bleeding (26), unintended pregnancy (21),
cramps/pain (11), and nausea/vomiting (11). There were 28 cases of
unduplicated ectopic pregnancies (none occurred in the USA) which are
discussed below. There were three unduplicated cases of convulsions, 10
cases of hypersensitivity, and 8 cases of possible pregnancy/fetal
effects.

> **a. Ectopic Pregnancy Risk:** With respect to pregnancy outcomes, the
> literature suggests an increased risk of ectopic pregnancy with
> progestin-only oral contraceptive pills that are taken on a regular
> daily basis. Based on the data from the sources discussed below there
> does not appear to be an increased risk of ectopic pregnancy with the
> use of levonorgestrel for emergency contraception or postcoital
> contraception.
>
> i\. [FDA Office of Drug Safety reported postmarketing
> review]{.underline}: there were 28 unduplicated cases of ectopic
> pregnancy; none were from the USA; there were no deaths; 15 patients
> were hospitalized, and 10 had surgery. There were 12 cases from Gideon
> Richter (manufacturer of levonorgestrel) in Hungary without
> information on the country of origin, 10 from the UK, 3 from Israel, 1
> from Sweden, China, and an unstated country.\
> \
> Postmarketing data are hard to interpret because 1) the denominator
> (number of drug exposures or total number of pregnancies) is unknown,
> 2) the likelihood of reporting ectopic pregnancies (a serious adverse
> event) is greater than the likelihood of reporting pregnancies (since
> a pregnancy is a product failure and not actually an adverse event),
> and 3) there is considerable underreporting of AEs in general.
>
> ii\. [Six large randomized clinical trials]{.underline} (RCTs)
> published in the medical literature: there are 7,893 evaluable
> subjects with 133 pregnancies and 2 ectopics, for an incidence of 1.5%
> ectopic pregnancies among total pregnancies. This is compelling data
> for the incidence of ectopic pregnancy associated with use of ECPs
> because RCTs are the \"gold standard\" with strict protocols and known
> numerators and denominators. The 1.5% incidence is consistent with the
> reported national rates of 12.4 and 19.7 per 1000 pregnancies \[range
> 1.24 to 2.0%\] in the UK and in the USA, respectively.[^3]^,^[^4]
> These 6 clinical trials provide evidence that levonorgestrel-only ECPs
> do not increase the chance that a pregnancy will be ectopic. Moreover,
> because ECPs are at least 75% effective in preventing a pregnancy,
> ECPs also reduce a woman\'s absolute risk of an ectopic pregnancy. The
> data from the RCTs is summarized in Table 1 below:\
> \
> **Table 1**.

  ----------------------------------------------------------------------------
  Randomized     Evaluable (n)  Pregnancies    Ectopic        Levonorgestrel
  Clinical Trial                               pregnancies    dose (mg)
                                               (n)            
  -------------- -------------- -------------- -------------- ----------------
  WHO 2002[^5]   1356           24             1              0.75- 2 doses

                 1356           20             0              1.5- single dose

  Arowojolu et   545            7              0              0.75- 2 doses
  al.[^6]                                                     

                 573            4              0              1.5- single dose

  WHO 1998[^7]   976            11             0              0.75- 2 doses

  Wu et al.[^8]  643            20             0              0.75- 2 doses

  Ho and         410            12             0              0.75- 2 doses
  Kwan[^9] 1993                                               

  Ho et al.      2,030          35             1              0.75- 2 doses
  2003[^10]                                                   

  **TOTAL**      **7,889**      **133**        **2**          
  ----------------------------------------------------------------------------

iii. Applicant [reported postmarketing]{.underline} (UK Medicines
     Control Agency and French Health Authority) and US reports
     (summarized in Table 2 below): there were 340 pregnancies and 21
     ectopic pregnancies (5.8%) reported to February 2003.[^11]

> Table 2.

+------------------+---------------+-----------------+-----------------+
| **Country**      | **            | **Ectopics**    | **Ectopic %**   |
|                  | Pregnancies** |                 | among total     |
|                  |               | **(N)**         | pregnancies     |
|                  | **(N)**       |                 |                 |
+------------------+---------------+-----------------+-----------------+
| France (2-03)    | 29            | 8               | 21%             |
+------------------+---------------+-----------------+-----------------+
| United Kingdom   | 201           | 12              | 5.6%            |
| (1-03)           |               |                 |                 |
+------------------+---------------+-----------------+-----------------+
| United States    | 110           | 1               | 0.9%            |
| (2-03)           |               |                 |                 |
+------------------+---------------+-----------------+-----------------+
| **TOTAL**        | **340**       | **21**          | **5.8%**        |
+------------------+---------------+-----------------+-----------------+

The [prescription]{.underline} label for Plan B has a subsection titled
**Ectopic Pregnancy** in the WARNINGS

Section. The following text is found in this section:

Ectopic pregnancies account for approximately 2% of reported pregnancies
(19.7 per 1000 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.

The [proposed OTC]{.underline} label for Plan B cautions women to be
alert for symptoms that could be indicative of an ectopic pregnancy.
There is no evidence that history of a previous ectopic pregnancy or
tubal disease is a contraindication to use of Plan B or that the risk of
an ectopic pregnancy is greater with the use of levonorgestrel emergency
contraception.

> **b. Fetal Risk:** In the original NDA, there were no reports of
> congenital abnormalities among women for whom the treatment failed or
> women mistakenly enrolled in studies who received the treatment after
> they were already pregnant. The FDA's ODS consultation found 3 cases
> of spontaneous abortion, 1 missed abortion, 1 inevitable abortion, and
> 3 reported European cases of congenital anomalies in pregnancies in
> women who had taken levonorgestrel ECPs. Given that spontaneous
> abortions have been reported to occur in 10-15% of clinically
> recognized pregnancies[^12], these reported events appear to be below
> the expected rate in the general population. In one congenital anomaly
> case, the woman also received abdominal X-rays at gestational week
> 12/40. With the applicant\'s estimated patient use of Plan B in 2.4
> million USA and 2.1 million UK women and the reduced risk of pregnancy
> of 1.1% in these women, one would expect \~49,500 unplanned
> pregnancies. These three reported cases are well below the expected
> 0.85% incidence of these congenital anomalies.[^13] It is unlikely
> that the Plan B exposure was a causative agent of the anomalies. The
> FDA did a review[^14] of the teratogenic risk of accidental use of
> contraceptive hormones early in pregnancy and concluded that there is
> not an association with adverse fetal or pregnancy outcomes. No
> studies have been large enough to quantify the teratogenic risk among
> the small number of pregnancies that follow the use of ECPs. However,
> observations that there is no increase in birth defects among
> pregnancies exposed to daily use of combined oral contraceptives are
> reassuring.[^15]
>
> **c. Allergic Reactions:** The ODS consultation for levonorgestrel
> emergency contraception identified ten unduplicated cases of
> hypersensitivity reactions, three of which occurred in the United
> States. Events ranged from minor localized rashes to urticaria, from
> localized edema to systemic edema, and included two cases of
> difficulty breathing \[one of those cases occurred in a woman who
> clearly had a history of an underlying pulmonary disorder given her
> list of concomitant medications (Buspar, Flovent, Singulaire,
> Seravent); so it is unclear whether the condition was levonorgestrel
> related\]. The time of onset was stated in 8 reports and ranged from 4
> hours to 2 days after taking the drug. Although 7 cases were marked
> \"life-threatening,\" none of the women stayed overnight in the
> hospital and the narratives provided in the reports did not clearly
> reflect a life-threatening event. Four of the women had taken
> concomitant medications, including 2 women on antibiotics, that could
> have caused the reported reactions.

**III. Misuse and Abuse:**

**A. Overdose:**

Overdosing is unlikely, since Plan B is packaged as a single course of
treatment and is relatively expensive. In clinical trials in Eastern
Europe between 1976-87 of women using up to 8 levonorgestrel 0.75 mg
tablets in a single menstrual cycle and up to four 0.75 mg tablets in a
single day, one SAE (an ectopic pregnancy) was reported. The
applicant\'s review of the Toxic Exposure Surveillance System (TESS)
found few reports on Plan B and none that resulted in death or serious
illness. In reviewing the medical literature on advance provision, there
were no cases of overdose or excessive use. There are no reports of any
person overdosing on this product in the Agency\'s AERS database.

**B. Repeat Use:**

Studies investigating how often women use ECPs have found that using it
more than four times in one year is uncommon. A study of general
practice patients in the UK found that less than one percent of ECPs
users requested ECPs more than three times a year.[^16] International
studies indicate that advance provision of ECPs does not lead women to
replace their regular method of contraception with ECPs. [^17]^-^[^18]
Studies show that women with easier access to ECPs are more likely to
use it when needed, potentially reducing unintended pregnancies and the
number of induced abortions.[^19]

Guidelines from the World Health Organization, American College of
Obstetricians and Gynecologists, and the American Society for Emergency
Contraception clearly state that although frequent use of ECPs is not
recommended, repeat use may be offered. There are no medical
contraindications (except allergy to levonorgestrel) to Plan B.

**C. Use During Pregnancy:**

There is no evidence that a woman's use of Plan B while she is pregnant
will result in abortion. Risk to the fetus if exposed to Plan B during
pregnancy was addressed in the Fetal Risk subsection of the Post
Marketing Safety section above, and in the appended review of
teratogenetic risk. The approved ECPs have been shown to inhibit
ovulation depending on when in the menstrual cycle they are taken. It is
believed that they may also interfere with the actual process of
fertilization by interfering with transport of the egg or sperm or with
the necessary changes that the sperm must undergo to be able to
fertilize an egg. Levonorgestrel, depending on dose and the time it is
administered in the menstrual cycle, does alter the endometrium, but
there is little direct evidence that interference with implantation is
the principal mechanism of action.[^20]^,^[^21] 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 clearly demonstrated, it is likely that the method works
primarily prior to fertilization. The fact that the method is more
effective the sooner it is used also argues against post-fertilization
modes of action. There is no clear evidence that ECPs will prevent
pregnancy after implantation and will interrupt an already-established
pregnancy.[^22] The inclusion of pregnancy as a contraindication in the
Plan B label is related not to safety, but to inform the consumer that
the product will not interrupt an established pregnancy.

IV. **Contraindications:**

There are no absolute contraindications to the use of hormonal emergency
contraception.[^23]

The labeled contraindications for [prescription]{.underline} Plan B
include 1) known or suspected pregnancy \[not a safety issue; listed
because the product will not interrupt a pregnancy\], 2)
hypersensitivity to any component of the product, and 3) undiagnosed
abnormal genital bleeding. These three conditions are listed in the
class label for progestin-only contraceptive pills that are taken daily
without interruption for routine contraception. The Plan B prescription
label states \"It is not known whether these same conditions apply to
the Plan B regimen consisting of the emergency use of two progestin
pills.\" The terms \'undiagnosed abnormal genital bleeding\' or
\'unexplained vaginal bleeding\' are not, in fact, a medically founded
contraindication for using Plan B; the applicant has proposed that this
condition be removed from the OTC label. The Reproductive Division
agrees with the applicant\'s request.

V.  **Safety of Advanced Provision and Pharmacy Provision**

Currently in the United States, Plan B is available by prescription from
a health care provider in all states, and directly from qualified
pharmacists (\"behind the counter\") in 5 states. Direct access from a
pharmacist was started as a pilot program in Washington in 1997.
Washington now has \~300 pharmacies with \~1,700 trained pharmacists in
the statewide program. Washington is the only state with government
reimbursement of a pharmacist for counseling associated with purchasing
ECPs. Other states with pharmacy provision of ECPs are California
(1-02), Alaska (3-02), New Mexico (12-02), and Hawaii (6-03).

Worldwide, levonorgestrel 0.75 mg tablets are now available in 101
countries[^24] and on a nonprescription basis from pharmacies in 33 of
these countries. ECPs are available over-the counter (OTC) in Norway,
Sweden and in at least three provinces[^25] in Canada.

The other method of easier access to ECPs is advanced prescription or
provision of the product. As access to ECPs becomes easier through
advance provision or pharmacy availability or possible OTC status,
several studies have concluded that greater availability does not result
in misuse or raise safety concerns in terms of serious adverse events,
hospitalization, or prolonged or severe labeled adverse events.[^26] To
date, there is no comprehensive study that has evaluated the USA
pharmacy experiences or has documented any safety concerns in that
setting.

**VII. Overall Safety Conclusions for Levonorgestrel ECPs:**

From an extensive review of published studies of RCTs, postmarketing
data, the medical literature, and large safety databases, it appears
that levonorgestrel emergency contraception pills, Plan B and the
identical products worldwide, have an acceptable margin of safety with a
low misuse and abuse potential. The individual can easily determine
their need for emergency contraception and the treatment is easy to use
(two tablets 12 hours apart for all women). There is no definite
contraindication to Plan B except an established allergy to
levonorgestrel, which has been rarely reported over the 25 years that
levonorgestrel has been taken by millions of women using a combination
hormonal oral contraceptive or ECPs containing levonorgestrel. There are
no clear dangers to a fetus or a pregnancy should the drug be taken when
a woman is already pregnant. This safety profile must be weighed against
the benefit that emergency contraception affords women a second chance
to avoid unwanted or unplanned pregnancies. Because emergency
contraception is more effective in preventing pregnancy the earlier it
is taken after unprotected sexual intercourse, over the counter status
should enhance benefit by providing more timely access to the product
than through prescription.[^27]

**VIII. Labeling Recommendations**

The applicant, in response to their Label Comprehension Study, made
labeling changes before the Actual Use Study was started. From a [safety
perspective]{.underline} the following labeling messages are
recommended:

-   Do not take Plan B if you are allergic to levonorgestrel or any
    ingredient in Plan B

-   Contact your health care provider if you experience the following:

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-   Severe stomach or pelvic pain, since this can be a warning sign of a
    tubal (ectopic) pregnancy

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```
-   No menstrual period in two weeks

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```
-   Any severe symptoms or symptoms that last more than 48 hours

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```
-   ECPs do not protect against sexually transmitted infections (STIs);
    condoms should be used if you are at risk for STIs

The Division of Reproductive and Urologic Drug Products agrees with the
applicant that these are critical messages for inclusion in the OTC
label, and also agrees that \"unusual or abnormal vaginal bleeding\" is
not a contraindication and should be removed from the label.

From an [efficacy perspective]{.underline} it is important for the label
to carry messages regarding appropriate timing of administration:

-   **ECPs should be taken as soon as possible after unprotected sex**,
    since ECPs are more effective the earlier they are
    initiated[^28]^,27^

-   The second dose should be taken 12 hours after the first dose

Timing of the second dose was one issue raised during the review of the
Actual Use Study. In the original NDA review, there were 37 pregnancies
(10 with levonorgestrel; 27 with Yuzpe); all of these subjects took
their second dose within 11-12 hours of the first dose. In contrast
there were 86 of 1955 evaluable subjects who took their second dose late
([by at least 6 hours]{.underline}) and none of these women became
pregnant. Only 7 of 1955 women did not take the second dose within 24
hours and none of these women became pregnant. There have been two
large, double-blind, randomized studies with 2712[^29] and 1118[^30]
evaluable women that compared administering levonorgestrel as a single
dose of 1.5 mg to the two dose 12-hour regimen of 0.75 mg
levonorgestrel. In both studies, the contraceptive effectiveness was
better in the single dose regimen (20/1356 and 4/573 pregnancies) than
in the two-dose regimen (24/1356 and 7/545 pregnancies). (See Table 3
below.) The single dose regimen was also shown to be safe, and the side
effects did not differ greatly between groups.

# Table 3

+------------------------+--------------------+------------------------+
| **Trial**              | **Single 1.5mg     | **Two 0.75mg doses (12 |
|                        | dose**             | hr)**                  |
|                        |                    |                        |
|                        | Pregnancies/       | Pregnancies/ evaluable |
|                        | evaluable N        | N                      |
+------------------------+--------------------+------------------------+
| Von Hertzen et al.     | 20/1356            | 24/1356                |
| (WHO 2002)             |                    |                        |
+------------------------+--------------------+------------------------+
| Arowojolu et al.       | 4/573              | 7/545                  |
+------------------------+--------------------+------------------------+

Timing of the first dose has also been examined. There have been two
studies that have limited data on taking the first dose at a later time
(72 to 120 hours). [^31]^,^[^32] Both studies showed that ECPs have a
favorable success rate [after]{.underline} 72 hours, with a pregnancy
rate that is lower than would be expected if no contraception were
administered.

These data support the conclusion that, although the recommended time
for the second dose is 12 hours, it can be taken sooner than 12 hours or
later (by at least 6 hours). There are also data in the literature that
suggest Plan B may be taken up to 5 days (120 hours) after unprotected
sexual intercourse.

Submitted by Daniel Davis, MD, MPH

Medical officer, DRUDP (HFD-580)

11-15-03

**Table 4 Studies of Levonorgestrel Taken After Intercourse for
Postcoital Contraception: Regimens Used**

+-------------------+---+--------------------------------------------------+
| **STUDY**         |   | **REGIMEN**                                      |
+===================+===+==================================================+
| **                |   |                                                  |
| WHO/HRP-sponsored |   |                                                  |
| multicenter       |   |                                                  |
| studies: single   |   |                                                  |
| 0.75 mg dose of   |   |                                                  |
| levonorgestrel**  |   |                                                  |
+-------------------+---+--------------------------------------------------+
| WHO/HRP 1987 --   |   | One 0.75 mg tablet within 8 hours after the      |
| Study 82906       |   | first coital act in the periovulatory period,    |
|                   |   | then one tablet 24 hours later, then one tablet  |
| International     |   | after each coital act, but no more than one      |
|                   |   | tablet per 24 hours.                             |
+-------------------+---+--------------------------------------------------+
| He, China 1991    |   | One 0.75 mg tablet within 8 hours after the      |
|                   |   | first coital act in the periovulatory period,    |
|                   |   | then one tablet 24 hours later, then one tablet  |
|                   |   | after each coital act, but no more than one      |
|                   |   | tablet per 24 hours.                             |
+-------------------+---+--------------------------------------------------+
| WHO/HRP 1993 --   |   | One 0.75 mg tablet within one hour after each    |
| Study 87908       |   | coital act, but no more than one tablet within a |
| International     |   | 3-hour period.                                   |
+-------------------+---+--------------------------------------------------+
| **Other studies   |   |                                                  |
| of                |   |                                                  |
| levonorgestrel,   |   |                                                  |
| 0.75 mg**         |   |                                                  |
+-------------------+---+--------------------------------------------------+
| Seregely, Hungary | O |                                                  |
|                   | n |                                                  |
| (multicenter      | e |                                                  |
| 16 small studies) | 0 |                                                  |
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|                   | . |                                                  |
+-------------------+---+--------------------------------------------------+
| Chernev           |   | One 0.75 mg tablet within one hour after each    |
|                   |   | coital act; no more than four tablets per month. |
| Bulgaria          |   |                                                  |
+-------------------+---+--------------------------------------------------+
| Szczurowicz,      |   | 0.75 mg tablets; up to 4 per cycle               |
| Poland            |   |                                                  |
+-------------------+---+--------------------------------------------------+
| Nirapathpongporn  |   | One 0.75 mg tablet within one hour after each    |
|                   |   | coital act, but no more than one tablet within   |
| Thailand          |   | any three hour period. In cases of multiple      |
|                   |   | acts, one tablet within one hour after the first |
|                   |   | act, a second tablet 3 hours later, and a third  |
|                   |   | tablet the next morning.                         |
+-------------------+---+--------------------------------------------------+
| Czekanowski       |   | One 0.75 mg tablet within one hour after each    |
|                   |   | coital act, but no more than one tablet within   |
| Poland            |   | any 3-hour period. In cases of multiple acts,    |
|                   |   | one tablet within one hour after the first act,  |
|                   |   | a second tablet 3 hours later, and a third       |
|                   |   | tablet the next morning.                         |
+-------------------+---+--------------------------------------------------+
| Klawe             |   | 0.75 mg tablets; regimen not stated.             |
|                   |   |                                                  |
| Hungary           |   |                                                  |
+-------------------+---+--------------------------------------------------+
| Orley             |   | One 0.75 mg tablet within one hour after         |
|                   |   | intercourse. In case of repeated intercourse,    |
| Hungary           |   | one more tablet three hours later.               |
+-------------------+---+--------------------------------------------------+
| Sas, Hungary      |   | One 0.75 mg tablet within one hour after each    |
|                   |   | coital act                                       |
+-------------------+---+--------------------------------------------------+
| **Other studies:  |   |                                                  |
| using various     |   |                                                  |
| dose levels of    |   |                                                  |
| levonorgestrel**  |   |                                                  |
+-------------------+---+--------------------------------------------------+
| Kesserü           |   | One tablet (0.15, 0.25, 0.30, 0.35, 0.40 mg)     |
|                   |   | within one hour after each coital act.           |
| Peru              |   |                                                  |
+-------------------+---+--------------------------------------------------+
| Moggia            |   | One 0.35 mg tablet within one hour after each    |
|                   |   | coital act.                                      |
| Argentina         |   |                                                  |
+-------------------+---+--------------------------------------------------+
| Echeverry         |   | 1.0 mg within 8 hours after intercourse, but no  |
|                   |   | more than one tablet in an 8 hour period         |
| Columbia          |   |                                                  |
+-------------------+---+--------------------------------------------------+
| Hurtado           |   | Various doses; regimens not stated. (Original    |
|                   |   | efficacy data from files of Schering A.G.)       |
| Peru              |   |                                                  |
+-------------------+---+--------------------------------------------------+
| Larrañaga, Peru   |   | One 1.0 mg tablet immediately after intercourse  |
+-------------------+---+--------------------------------------------------+
| Canzler           |   | Group A: One 0.4 mg tablet within 12 hours after |
|                   |   | each coital act.                                 |
| East Germany      |   |                                                  |
|                   |   | Group B: Two 0.25 mg tablets immediately before  |
|                   |   | and one 0.25 mg tablet 8 hours after each coital |
|                   |   | act                                              |
+-------------------+---+--------------------------------------------------+

[^1]: Current NDA submission, Volume 9, page 116.

[^2]: The ODS Postmarketing Safety Review dated October 31, 2003is
    attached: see Subsection B

[^3]: Rajkhowa M, et al. Trends in the incidence of ectopic pregnancy in
    England and Wales from 1966 to 1996. *Br J Obstet Gyn*
    2000;107:369-74.

[^4]: Ectopic pregnancies: USA data, 1990 to 1992. *Morb Mortal Wkly
    Report* 1995;44:46-48.

[^5]: von Hertzen H, et al. Low dose mifepristone and two regimens of
    levonorgestrel for emergency contraception: a WHO multicenter
    randomized trial. *Lancet* 2002;360:1803-10.

[^6]: Arowojolu AO, et al. Comparative evaluation of the effectiveness
    and safety of two regimens of levonorgestrel for emergency
    contraception in Nigerians. *Contraception* 2002;66:269-73.

[^7]: Task Force on Post-ovulatory Methods of Fertility Regulation.
    Randomized controlled of levonorgestrel versus Yuzpe regimen of
    combined oral contraceptives for emergency contraception. *Lancet*
    1998;352:428-433.

[^8]: Wu S, et al. A randomized, double-blind, multicenter study on
    comparing levonorgestrel and mifepristone for emergency
    contraception \[in Chinese\]. *Zhonghua Fu Chan Ke Za Zhi*
    1999;34:327-30. In *J of Fam Plan and Repro Health Care*
    2003;29(4):249.

[^9]: Ho PC, Kwan MSW. A prospective randomized comparison of
    levonorgestrel and the Yuzpe regimen in post-coital contraception.
    *Hum Reprod* 1993;8:389-92.

[^10]: NDA submission, Volume 13/59, pages 047-048j. \[13 pages\]

[^11]: Current NDA submission, Volume 9, page 119.

[^12]: ACOG Practice Bulletin, Clinical Management Guidelines for
    Obstetrician-Gynecologists; February 2001, No. 24: 1.

[^13]: ACOG Practice Bulletin. Prenatal Diagnosis of Fetal Chromosomal
    Abnormalities. May 2001; No. 27:1‑11.

[^14]: See appended report dated June 26, 2002: Subsection C.

[^15]: Bracken MB. Oral contraception and congenital malformations in
    offspring: a review and meta-analysis of the prospective studies.
    *Obstetrics Gynecology* 1990;76:552-57.

[^16]: Rowlands S, Lawrenson R. Repeated use of hormonal emergency
    contraception by younger women in the UK. *Br J Fam Plan*
    2000;26:138-43.

[^17]: Glasier A, Baird D. The effects of self-administering emergency
    contraception. *NEJM* 1998;339(1):1-4.

[^18]: Turner AN, Ellertson C. How safe is emergency contraception?
    *Drug Safety* 2002;25(10):695-706.

[^19]: Grimes DA. Correspondence: replies. *NEJM* 2003;348(1):83.

[^20]: Marions L, et al. Emergency contraception with mifepristone and
    Levonorgestrel: Mechanism of Action. *Obstetrics nd Gynecology* July
    2002;100(1):65-71.

[^21]: Durand, M, et al. On the mechanisms of action of short-term
    levonorgestrel administration in emergency contraception.
    *Contraception* 2001;64:227-34.

[^22]: Rivera R, et al. The mechanism of action of hormonal
    contraceptives and IUDs. AJOG Reviews. *Am J Obstetrics Gynecology*
    1999;181(5):1263-69.

[^23]: Westoff C. Emergency Contraception: clinical practice. *NEJM*
    November 6, 2003;349:1830-35.

[^24]: Applicant Advisory Committee Briefing Document.

[^25]: Email sent to Vyta Senikas, Exec. VP, The Society of Ob/Gyn of
    Canada, on 10-24-03 for further details.

[^26]: See FDA Review of Behavior Study Literature and applicant\'s
    Integrated Summary of Safety (Volume 9 of 59 volume NDA submission.

[^27]: This conclusion was clearly demonstrated in the FDA review of the
    original efficacy data from the comparative WHO multicenter Study
    92808 submitted in the Plan B application in 1999, and has been
    substantiated by several articles in the peer-reviewed medical
    literature.

[^28]: Task Force on Post-Ovulatory Methods of Fertility Regulation.
    Randomized controlled trial of levonorgestrel versus the Yuzpe
    regimen of combination oral contraceptives for emergency
    contraception. *Lancet.* 1998; 352:428-33.

[^29]: Von Hertzen H, et al. *Op. cit. Lancet* 2002(Dec).

[^30]: Arowojolu AO, et al. *Op. cit. Contraception* 2002

[^31]: Von Hertzen H, et al. Low dose mifepristone and two regimens of
    levonorgestrel for emergency contraception: a WHO multicenter
    randomized trial. *Lancet* 2002(Dec.);360:1803-10.

[^32]: Rodrigues J, et al. Effectiveness of ECPs between 72 and 120
    hours after unprotected sexual intercourse. *Am J Obstetrics
    Gynecology* 2001;184:531-37.