+-----------------+----------------------------------------------------+
| ######          | **DEPARTMENT OF HEALTH AND HUMAN SERVICES**        |
|  **MEMORANDUM** |                                                    |
|                 | **PUBLIC HEALTH SERVICE**                          |
|                 |                                                    |
|                 | ######### FOOD AND DRUG ADMINISTRATION             |
|                 |                                                    |
|                 | **CENTER FOR DRUG EVALUATION AND RESEARCH**        |
+-----------------+----------------------------------------------------+

DATE: February 2, 2004

TO: Paul Seligman, M.D., M.P.H., Acting Director

Anne Trontell, M.D., M.P.H., Deputy Director

Office of Drug Safety

> Immediate Office, HFD-400

THROUGH: Mark Avigan, M.D., C.M., Director

Office of Drug Safety

Division of Drug Risk Evaluation, HFD-430

FROM: Marilyn Pitts, Pharm.D., Safety Evaluator

Claudia B. Karwoski, Pharm.D., Safety Evaluator Team Leader

Office of Drug Safety

Division of Drug Risk Evaluation, HFD-430

SUBJECT: PID D030417

Drug: Isotretinoin

Topic: Pregnancy Exposures

EXECUTIVE SUMMARY

This document summarizes a review of pregnancy exposure data reported to
FDA in women treated with isotretinoin. The goal of this review was to
compare isotretinoin pregnancy exposure data during the year prior to
the implementation of the enhanced Isotretinoin Risk Management Program
(Pre-RMP) to the first year of implementation of the enhanced RMP
(Post-RMP).

It is important to keep in mind that the data for these analyses are
primarily based on spontaneous reporting to passive surveillance systems
such as AERS and are subject to reporting bias. It is possible for
instance, that there was an increase in the reporting of pregnancies in
the Post-RMP year, due to publicity around the implementation of the
RMP. Additionally spontaneous reports are variable in quality and
completeness; as such, lack of information does not necessarily indicate
lack of compliance with the RMP. Furthermore, experience of pregnancy
failures may not represent general experience of isotretinoin users.

The review of the pregnancy exposure data comparing the Pre-RMP to the
Post-RMP period can by summarized as follows:

-   One hundred twenty-seven (127) pregnancy exposures occurred during
    the Pre-RMP year and 120 cases occurred during the Post-RMP year.
    These numbers do not reflect an appreciable decrease in pregnancies
    with the enhanced RMP and may in fact reflect an increase relative
    to the overall decline in use of isotretinoin in the year following
    the implementation of the RMP.[^1]

-   The number of women who were already pregnant prior to initiating
    therapy with isotretinon is small and declined during the Post-RMP
    period relative to the Pre-RMP period (Pre-RMP-12, Post-RMP-7).

-   Pregnancies occurred throughout isotretinoin treatment for both
    Pre-RMP and Post-RMP periods. Although more pregnancies occurred
    during the first month of isotretinoin use compared to other months
    (\~15-19%), the aggregate number of pregnancies that occurred after
    the first month of isotretinoin therapy was greater than in the
    first month (\~42-53%).

-   The number of days of exposure to isotretinoin following conception
    has not changed between the Pre-RMP or Post-RMP periods.

-   There has been no improvement in baseline pregnancy testing (49.6%
    and 50% for Pre-RMP and Post-RMP, respectively) and only a slight
    improvement in monthly pregnancy testing (35.4% and 39.1% for
    Pre-RMP and Post-RMP, respectively) and in the use of at least one
    method of birth control (53.5% and 58.3% for Pre-RMP and Post-RMP,
    respectively) among patients who became pregnant during the Pre-RMP
    period versus the Post-RMP period.

Although the actual reason that the pregnancies occurred could not be
delineated from the cases in the series, some common themes were
identified and could account for the pregnancy failures. These are
summarized below:

-   Twenty-one women were not using any form of contraception when the
    exposed pregnancy occurred or chose abstinence as a means of
    contraception and then went on to engage in unprotected sexual
    intercourse.

-   Only 15% of women reporting birth control information reported use
    of "appropriate" birth control consisting of two methods, at least
    one of which was a primary method.

-   Thirty-eight percent (38%) of women who reported using at least one
    form of contraception reported non-compliance with their chosen
    method of contraception. Non-compliant women either discontinued use
    of birth control early, missed doses of their oral contraceptive, or
    used contraception inconsistently.

-   An evaluation of isotretinoin treatment start dates in relation to
    first day of the last menstrual period (LMP) and baseline pregnancy
    testing among 16 of 20 patients who were pregnant prior to
    initiating therapy with isotretinoin was performed.

    -   Only two reported a baseline pregnancy test during the LMP.

    -   None of the 16 patients started isotretinoin within two weeks of
        their LMP. Although the label does not instruct to start within
        a specified period of time around the LMP, it does state that
        the baseline pregnancy test should be conducted during the first
        five days of menses immediately preceding isotretinoin therapy,
        and that the prescription for isotretinoin should be dispensed
        within 7 days of the "qualification date" or confirmatory
        pregnancy test

```{=html}
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```
-   Seven women took isotretinoin without medical supervision. In five,
    the patients saved isotretinoin and restarted for an acne flare, one
    obtained isotretinoin at a swap meet, and one obtained a
    prescription in January but did not take until December of the same
    year.

The outcome of the pregnancy is unknown in almost half of all the
pregnancy cases reviewed. As would be expected, this percentage is
higher in the Post-RMP cases where outcomes may not yet have occurred or
been reported. Sixty-seven percent (113/160) of those that reported
pregnancy outcome information elected to terminate the pregnancy.
Twenty-nine women delivered a live born infant and a small number of
these cases reported a congenital anomaly.

In summary, the number of pregnancy exposures has not decreased
appreciably and may have increased relative to the overall decrease in
use of isotretinoin in the year following the implementation of the
enhanced Isotretinoin Risk Management Program. Our review of a number of
parameters comparing the Pre-RMP to the Post-RMP suggest minimal or no
improvement with the implementation of the RMP. However, it should be
emphasized that pre-specified pregnancy exposure metrics were not
defined and that the experience of pregnancy failures may not represent
general experience of isotretinoin users.

**[METHODS]{.underline}**

All pregnancy cases submitted to the Agency after April 1, 2001 from the
following sources were reviewed[^2]:

-   Reported directly to isotretinoin manufacturers (Roche, Genpharm
    (Mylan distributor), and Barr)

-   Reported to the manufacturers via the isotretinoin patient surveys
    (Slone and SI Degge)

-   Reports in the Adverse Event Reporting System (AERS)

    **Inclusion Criteria**

Cases were included if they met the following criteria:

-   Maternal fetal exposure to isotretinoin

-   Isotretinoin administered orally

-   Fetal exposure occurred during isotretinoin's use, or

-   [\<]{.underline} 30 days after isotretinoin discontinuation

-   Estimated conception occurred during the following RMP phases
    (categories):

    -   **Pre-RMP**: conception occurred between 4/1/01 to 3/31/02,
        including cases received by Roche, FDA, SI, Slone, generics by
        8/15/02

    -   **Post-RMP**: conception occurred between 4/1/02 to 3/31/03,
        including cases received by Roche, FDA, SI, Slone, generics by
        8/15/03

    -   **Unknown:** Conception date could not be determined but case
        was received from April 1, 2001 to August 15, 2003.

        **[RESULTS]{.underline}**

Eight hundred and eight (808) cases from all sources were reviewed. Four
hundred eighty-three cases were excluded for the following reasons:

-   Conception occurred prior to April 1, 2001 -- 255

-   Conception occurred after March 31, 2003 -- 36

-   Paternal-fetal exposures -- 35

-   Conception occurred more than 30 days following discontinuation of
    isotretinoin -- 78

-   Conception occurred during the Pre-RMP period but was received after
    August 15, 2002 -- 40

-   Conception occurred during the Post-RMP period but was received
    after August 15, 2003 -- 1

-   Conception occurred an unknown period following isotretinoin
    discontinuation -- 11

-   Non-pregnancy related cases -- 9

-   Pregnancy in mothers exposed to isotretinoin by touch -- 2

-   Duplicate case -- 15

-   No patient identified -- 1

    **1. GENERAL SUMMARY INFORMATION**

Three hundred twenty-five pregnancy exposures from all sources met the
inclusion criteria.

The following table provides general information about the pregnancy
exposures.

  ----------------------------------------------------------------------------------
  **Table 1.                                                           
  General                                                              
  Information                                                          
  Regarding                                                            
  Pregnancy                                                            
  Exposures**                                                          
  ------------- -------------------------- ------------- ------------- -------------
                                           Pre-RMP       Post-RMP      Unknown

  **Number of                              127           120           78
  pregnancy                                                            
  exposures**                                                          

                **During isotretinoin**    95 (74.8%)    87 (72.5%)    67 (85.9%)

                **Within 30 days after     31 (24.4%)    31 (25.8%)    7 (9%)
                isotretinoin**                                         

                **Indeterminate**          1 (0.8%)      2 (1.7%)      4 (5.1%)

  **Trimester                                                          
  exposed**                                                            

                **First**                  123           112           28

                **First and second**       1             0             0

                **Unknown**                3             8             50

  **Age                                    n=111         n=101         n=27
  (years)**                                                            

                **Mean**                   22.7          24.1          25

                **Median**                 24            23            24

                **Range**                  14-36         14-42         15-50
  ----------------------------------------------------------------------------------

One hundred twenty-seven cases were determined to have occurred during
the year prior to the implementation of the enhanced RMP (Pre-RMP). One
hundred twenty cases were determined to have occurred during the first
year of implementation of the enhanced RMP (Post-RMP). Seventy-eight
cases could not be categorized because the conception date was not
reported and could not be estimated. The majority of the pregnancy
exposures in all three categories occurred during the use of
isotretinoin and during the first trimester of pregnancy. There was no
difference in the median age of the women among all three categories.

**1.1 Pregnancy Exposures by Report Source**

Table 2 shows the pregnancy cases by report source. Pregnancy cases are
voluntarily reported either directly to the manufacturers or to the FDA.
They may also be reported via the Isotretinoin Patient Surveys.

+----------------+-----------+-----------+--------------+------------+
| **Table 2.     |           |           |              |            |
| Report Source  |           |           |              |            |
| of Pregnancy   |           |           |              |            |
| Exposure       |           |           |              |            |
| Reports        |           |           |              |            |
| included in    |           |           |              |            |
| analysis**     |           |           |              |            |
+================+===========+===========+==============+============+
| **Source**     | Pre-RMP   | Post-RMP  | Unknown      | Total      |
|                |           |           | Conception   |            |
|                |           |           | Date         |            |
+----------------+-----------+-----------+--------------+------------+
| Slone          | 25        | 20        | 0            | 45         |
|                |           |           |              |            |
| SI/Degge       | 0         | 12        | 6            | 18         |
+----------------+-----------+-----------+--------------+------------+
| Total          | 25        | 32        | 6            | 63         |
| Isotretinoin   |           |           |              |            |
| Survey         |           |           |              |            |
+----------------+-----------+-----------+--------------+------------+
| Direct to      | 99        | 86        | 72           | 257        |
| Manufacturer   |           |           |              |            |
+----------------+-----------+-----------+--------------+------------+
| Direct to FDA  | 3         | 2         | 0            | 5          |
+----------------+-----------+-----------+--------------+------------+
| **Total        | 127       | 120       | 78           | 325        |
| Cases**        |           |           |              |            |
+----------------+-----------+-----------+--------------+------------+

-   The majority of Pre-RMP and Post-RMP cases were reported directly to
    the manufacturer.

-   Twenty percent (25/127) of the Pre-RMP cases and 27% (32/120) of the
    Post-RMP cases were reported by the isotretinoin patient survey
    conducted by the Slone Epidemiology Unit, and/or Degge/SI.

We attempted to determine whether any particular source provided more
complete and better quality data (e.g. isotretinoin survey versus
directly to manufacturer). Table 3 shows the number of data elements
completed in the pregnancy exposure reports, stratified by source of the
report.

+------------+-------------+-------------+-------------+--------------+
| **Table 3. |             |             |             |              |
| Report     |             |             |             |              |
| Data       |             |             |             |              |
| Elements   |             |             |             |              |
| completed  |             |             |             |              |
| in         |             |             |             |              |
| Pregnancy  |             |             |             |              |
| Exposure   |             |             |             |              |
| Cases      |             |             |             |              |
| included   |             |             |             |              |
| in         |             |             |             |              |
| analysis** |             |             |             |              |
+============+=============+=============+=============+==============+
| **Source** | Pre-RMP     | Post-RMP    | Unknown     | Overall      |
|            |             | (n=120)     | (n=78)      |              |
|            | (n=127)     |             |             |              |
+------------+-------------+-------------+-------------+--------------+
| **Total    | Range: 6 to | Range: 3 to | Range: 3 to | Range: 3 to  |
| Is         | 11,         | 11, median  | 6, median=4 | 11, median=7 |
| otretinoin | median=8    | 7 (n=32)    | (n=6)       | (n=63)       |
| Survey**   | (n=5)       |             |             |              |
+------------+-------------+-------------+-------------+--------------+
| **Direct   | Range: 1 to | Range: 1 to | Range: 0 to | Range: 0 to  |
| to         | 11,         | 11,         | 6, median=1 | 11, median=5 |
| Manu       | median=6    | median=6    | (n=72)      | (n=257)      |
| facturer** | (n=99)      | (n= 86)     |             |              |
+------------+-------------+-------------+-------------+--------------+
| **Direct   | Range: 3 to | Range: 3 to | \-\-\-\-\-- | Range: 3 to  |
| to FDA**   | 5, median=  | 9, median=6 |             | 9, median=4  |
|            | 4 (n=3)     | (n=2)       |             | (n=5)        |
+------------+-------------+-------------+-------------+--------------+

The data elements that were assessed included:

-   Any baseline pregnancy information

-   Any contraceptive information

-   Any contraceptive compliance information

-   The mother's age

-   Any pregnancy testing during treatment information

-   The last menstrual period date

-   Isotretinoin therapy dates

-   Estimated conception date

-   Gestational age of the fetus

-   Pregnancy outcome information

-   Fetal outcome information

Overall, reports submitted by the patient surveys contained more data
elements (median = 7) than reports submitted either by the manufacturer
(median = 5), or reports submitted directly to the FDA (median = 4). It
is not clear whether greater attempts for follow-up information occur in
those pregnancy cases reported to the patient surveys.

It is important to note that the data elements assessed in these reports
do not directly measure compliance with Isotretinoin Risk Management
Program parameters as listed in the Hoffmann-La Roche, *1 Year Report on
the S.M.A.R.T. Program*[^3] which include the following:

-   Signed General Informed Consent

-   Signed Female Informed Consent

-   Received Spiral Notebook

-   Received Instruction for Accutane Survey

-   Enrolled in Accutane Survey

-   Two Baseline Pregnancy Tests

-   Monthly Follow-up Pregnancy Tests

-   Yellow Sticker Attached to Rx

-   Used two forms of contraception

    **1.2 Pregnancy Cases by Quarter**

Cases by the conception date quarter for both Pre-RMP and Post-RMP cases
were examined. Analysis of the number of pregnancies by quarter for the
Post-RMP year was performed to determine whether there has been a
decline in the number of cases over time after the implementation of the
RMP (Table 4). In addition a comparison of each Post-RMP quarter
relative to the same Pre-RMP quarter was made (Table 5).

  -----------------------------------------------------------------------
  **Table 4.            
  Isotretinoin          
  Pregnancy Cases by    
  Quarter for the       
  Post-RMP Periods as a 
  Percentage of Total** 
  --------------------- -------------------------------------------------
                        Pregnancies (% of total)

  **Quarter 1**         26 (22%)

  **Quarter 2**         29 (24%)

  **Quarter 3**         19 (16%)

  **Quarter 4**         19 (16%)

  **Unknown\***         27 (23%)

  \*actual quarter      
  conception occurred   
  could not be          
  determined in all     
  Post-RMP cases        
  -----------------------------------------------------------------------

There were fewer cases reported during the last two quarters of the
Post-RMP period compared to the first two quarters. It's not clear
whether this decrease is due to improved compliance with the enhanced
RMP over time, less follow-up time compared to earlier quarter, and/or
whether this decline will continue into the second year following
implementation of the RMP.

+-------------------+-----------+-----------+-----------+-----------+
| **Table 5.        |           |           |           |           |
| Isotretinoin      |           |           |           |           |
| Pregnancy Cases   |           |           |           |           |
| by Quarter**      |           |           |           |           |
+===================+===========+===========+===========+===========+
|                   | **Quarter | **Quarter | **Quarter | **Quarter |
|                   | 1**       | 2**       | 3**       | 4**       |
|                   |           |           |           |           |
|                   | **(Apr 1  | **(Jul 1  | **(Oct 1  | **(Jan 1  |
|                   | -- Jun    | -- Sep    | -- Dec    | -- Mar    |
|                   | 30)**     | 30)**     | 31)**     | 31)**     |
+-------------------+-----------+-----------+-----------+-----------+
| **Pre-RMP (n =    | 37        | 27        | 18        | 28        |
| 110)\***          |           |           |           |           |
+-------------------+-----------+-----------+-----------+-----------+
| **Post-RMP (n =   | 26        | 29        | 19        | 19        |
| 93)\***           |           |           |           |           |
+-------------------+-----------+-----------+-----------+-----------+
| **Percent Change  | \- 30%    | \+ 7%     | \+ 5.5%   | \- 32%    |
| from Pre-RMP to   |           |           |           |           |
| Post-RMP**        |           |           |           |           |
+-------------------+-----------+-----------+-----------+-----------+
| \*actual quarter  |           |           |           |           |
| conception        |           |           |           |           |
| occurred could    |           |           |           |           |
| not be determined |           |           |           |           |
| in all Pre-RMP    |           |           |           |           |
| and Post-RMP      |           |           |           |           |
| cases             |           |           |           |           |
+-------------------+-----------+-----------+-----------+-----------+

When each Post-RMP quarter was compared to the same Pre-RMP quarter,
variations in all examined quarters were found. Variations between the
quarters ranged from increased reporting of pregnancies by 7% in the
second quarter to decreased reporting by 32% in the fourth quarter. The
variations between quarters were not necessarily reflected by the change
in use patterns over that same time frame (Table 6). Please see the Drug
Utilization Review[^4] for more comprehensive isotretinoin usage
information.

+-------------------+-----------+-----------+-----------+-----------+
| **Table 6.        |           |           |           |           |
| Isotretinoin      |           |           |           |           |
| Prescriptions     |           |           |           |           |
| Dispensed by      |           |           |           |           |
| Quarter (in       |           |           |           |           |
| thousands)**      |           |           |           |           |
+===================+===========+===========+===========+===========+
|                   | **Quarter | **Quarter | **Quarter | **Quarter |
|                   | 1**       | 2**       | 3**       | 4**       |
|                   |           |           |           |           |
|                   | **(Apr 1  | **(Jul 1  | **(Oct 1  | **(Jan 1  |
|                   | -- Jun    | -- Sep    | -- Dec    | -- Mar    |
|                   | 30)**     | 30)**     | 31)**     | 31)**     |
+-------------------+-----------+-----------+-----------+-----------+
| **Pre-RMP**       | 377       | 338       | 394       | 398       |
+-------------------+-----------+-----------+-----------+-----------+
| **Post-RMP**      | 295       | 248       | 293       | 325       |
+-------------------+-----------+-----------+-----------+-----------+
| **Percent Change  | \- 22%    | \- 27%    | \- 26%    | \- 18%    |
| from Pre-RMP to   |           |           |           |           |
| Post-RMP**        |           |           |           |           |
+-------------------+-----------+-----------+-----------+-----------+
| US Data Source:   |           |           |           |           |
| IMS Health, IMS   |           |           |           |           |
| National          |           |           |           |           |
| Prescription      |           |           |           |           |
| Audit Plus™; for  |           |           |           |           |
| 4/01 to 3/03;     |           |           |           |           |
| accessed November |           |           |           |           |
| 7, 2003.          |           |           |           |           |
+-------------------+-----------+-----------+-----------+-----------+

**1.3 Estimated Timing of Conception**

The following table shows the estimated timing of conception relative to
the isotretinoin treatment course. This was based on the most recent
treatment course around the pregnancy.

+----------------+------------+------------+------------+------------+
| **Table 7.     |            |            |            |            |
| Estimated      |            |            |            |            |
| timing\* of    |            |            |            |            |
| conception in  |            |            |            |            |
| women that     |            |            |            |            |
| became         |            |            |            |            |
| pregnant       |            |            |            |            |
| during         |            |            |            |            |
| isotretinoin   |            |            |            |            |
| treatment**    |            |            |            |            |
+================+============+============+============+============+
| **Treatment    | Pre-RMP    | Post-RMP   | Unknown    | All cases  |
| Month**        |            |            | (n=67)     | (n=249)    |
|                | (n=95)     | (n=87)     |            |            |
+----------------+------------+------------+------------+------------+
| **Prior to     | 12 (12.6%) | 7 (8%)     | 1 (1.5%)   | 20 (8.0%)  |
| t              |            |            |            |            |
| reatment\*\*** |            |            |            |            |
+----------------+------------+------------+------------+------------+
| **During 1st   | 18 (18.9%) | 13 (14.9%) | 1 (1.5%)   | 32 (12.9%) |
| month**        |            |            |            |            |
+----------------+------------+------------+------------+------------+
| **During 2nd   | 7 (7.3%)   | 7 (8 %)    | 0          | 14 (5.6%)  |
| month**        |            |            |            |            |
+----------------+------------+------------+------------+------------+
| **During 3rd   | 7 (7.3%)   | 7 (8 %)    | 2 (3%)     | 16 (6.4%)  |
| month**        |            |            |            |            |
+----------------+------------+------------+------------+------------+
| **During 4th   | 8 (8.4%)   | 15 (17.2%) | 1 (1.5%)   | 23 (9.2%)  |
| month**        |            |            |            |            |
+----------------+------------+------------+------------+------------+
| **During 5th   | 7 (7.3%)   | 5 (5.7%)   | 0          | 12 (4.8%)  |
| month**        |            |            |            |            |
+----------------+------------+------------+------------+------------+
| **During 6th   | 8 (8.4%)   | 5 (5.7%)   | 0          | 13 (5.2%)  |
| month**        |            |            |            |            |
+----------------+------------+------------+------------+------------+
| **\> 6         | 3 (3.1%)   | 7 (8 %)    | 1 (1.5%)   | 11(4.4%)   |
| months**       |            |            |            |            |
+----------------+------------+------------+------------+------------+
| **I            | 25 (26.3%) | 21 (24.1%) | 61 (91%)   | 107 (43%)  |
| ndeterminate** |            |            |            |            |
+----------------+------------+------------+------------+------------+
| \*Based on     |            |            |            |            |
| isotretinoin   |            |            |            |            |
| start date to  |            |            |            |            |
| conception or  |            |            |            |            |
| positive       |            |            |            |            |
| pregnancy      |            |            |            |            |
| test; assuming |            |            |            |            |
| a 30 day       |            |            |            |            |
| treatment      |            |            |            |            |
| period         |            |            |            |            |
|                |            |            |            |            |
| \*\*           |            |            |            |            |
| Percentage is  |            |            |            |            |
| based on the   |            |            |            |            |
| number of when |            |            |            |            |
| who became     |            |            |            |            |
| pregnant       |            |            |            |            |
| during         |            |            |            |            |
| isotretinoin   |            |            |            |            |
| treatment;     |            |            |            |            |
| percentage is  |            |            |            |            |
| lower if       |            |            |            |            |
| applied to     |            |            |            |            |
| women who      |            |            |            |            |
| became         |            |            |            |            |
| pregnant       |            |            |            |            |
| during and     |            |            |            |            |
| within 30 days |            |            |            |            |
| of             |            |            |            |            |
| d              |            |            |            |            |
| iscontinuation |            |            |            |            |
| of             |            |            |            |            |
| isotretinoin.  |            |            |            |            |
+----------------+------------+------------+------------+------------+

For the 249 patients (of 325 total) that became pregnant during
isotretinoin therapy, there were more reported pregnancies in the first
month of isotretinoin therapy relative to subsequent individual months
(15-19%); however the aggregate number of pregnancies that occurred
after the first month of isotretinoin therapy was greater (\~42-53%).

**1.4 Days Exposure to Isotretinoin Following Conception**

The following tables show the days of exposure to isotretinoin following
conception. This is based on the estimated conception date to the day
that isotretinoin was discontinued.

+----------------+-----------------+-----------------+-----------------+
| **Table 8.     |                 |                 |                 |
| Days Exposure  |                 |                 |                 |
| to             |                 |                 |                 |
| Isotretinoin   |                 |                 |                 |
| Following      |                 |                 |                 |
| Conception**   |                 |                 |                 |
+================+=================+=================+=================+
|                | Pre-RMP         | Post-RMP        | Unknown         |
+----------------+-----------------+-----------------+-----------------+
| Range          | 1 to 91 days    | 1 to 52 days    | 3 to 105 days   |
|                |                 |                 |                 |
| Mean           | 19.1 days       | 19.3 days       | 26.1 days       |
|                |                 |                 |                 |
| Median         | 17 days         | 17 days         | 14 days         |
|                |                 |                 |                 |
|                | (n=71)          | (n=54)          | (n=8)           |
+----------------+-----------------+-----------------+-----------------+

There was no difference in mean and median number of days exposed to
isotretinoin following conception between the Pre-RMP and Post-RMP year.
The following table shows these same data in ranges of days.

  ------------------------------------------------------------------------
  **Table 9. Days Exposure to                               
  Isotretinoin Following                                    
  Conception**                                              
  ----------------------------- ------------ -------------- --------------
                                Pre-RMP      Post-RMP       Unknown

  **\<7 days**                  15 (15.7%)   11 (12.6%)     2 (3%)

  **7 to 14 days**              18 (18.9%)   9 (10.3%)      2 (3%)

  **15 to 30 days**             27 (28.4%)   21 (24.1%)     2 (3%)

  **\> 30 days**                11 (11.6%)   13 (14.9%)     2 (3%)

  **Number of days exposure     24 (25.2%)   33 (38%)       59 (88%)
  unknown**                                                 

  **Total number during         95           87             67
  isotretinoin**                                            
  ------------------------------------------------------------------------

The percentage of pregnant patients exposed to isotretinoin for greater
than two weeks has not changed from Pre-RMP to Post-RMP (40%; 38/95 and
39%; 34/87, for Pre-RMP and Post-RMP periods, respectively).

**2. PREGNANCY TESTING**

**2.1 Baseline Pregnancy Testing Prior to Starting Isotretinoin**

Two (urine or serum) baseline pregnancy tests, prior to starting
isotretinoin therapy are mandated in the product label.

An evaluation of how often any baseline pregnancy testing was performed
before starting isotretinoin therapy was performed. Any baseline
pregnancy testing is defined as pregnancy testing occurring before
starting isotretinoin therapy. Information on the type of pregnancy test
(urine or serum) was inconsistently reported, therefore making it
impossible to reliably determine the type of pregnancy test that
occurred. A comparison of Pre-RMP data with Post-RMP data was made.

+---+-----------------------+--------------------+----------------------+
| * |                       |                    |                      |
| * |                       |                    |                      |
| T |                       |                    |                      |
| a |                       |                    |                      |
| b |                       |                    |                      |
| l |                       |                    |                      |
| e |                       |                    |                      |
| 1 |                       |                    |                      |
| 0 |                       |                    |                      |
| . |                       |                    |                      |
| B |                       |                    |                      |
| a |                       |                    |                      |
| s |                       |                    |                      |
| e |                       |                    |                      |
| l |                       |                    |                      |
| i |                       |                    |                      |
| n |                       |                    |                      |
| e |                       |                    |                      |
| P |                       |                    |                      |
| r |                       |                    |                      |
| e |                       |                    |                      |
| g |                       |                    |                      |
| n |                       |                    |                      |
| a |                       |                    |                      |
| n |                       |                    |                      |
| c |                       |                    |                      |
| y |                       |                    |                      |
| T |                       |                    |                      |
| e |                       |                    |                      |
| s |                       |                    |                      |
| t |                       |                    |                      |
| i |                       |                    |                      |
| n |                       |                    |                      |
| g |                       |                    |                      |
| w |                       |                    |                      |
| h |                       |                    |                      |
| i |                       |                    |                      |
| l |                       |                    |                      |
| e |                       |                    |                      |
| u |                       |                    |                      |
| s |                       |                    |                      |
| i |                       |                    |                      |
| n |                       |                    |                      |
| g |                       |                    |                      |
| I |                       |                    |                      |
| s |                       |                    |                      |
| o |                       |                    |                      |
| t |                       |                    |                      |
| r |                       |                    |                      |
| e |                       |                    |                      |
| t |                       |                    |                      |
| i |                       |                    |                      |
| n |                       |                    |                      |
| o |                       |                    |                      |
| i |                       |                    |                      |
| n |                       |                    |                      |
| * |                       |                    |                      |
| * |                       |                    |                      |
+===+=======================+====================+======================+
|   |                       | **Pre-RMP n =      | **Post-RMP**         |
|   |                       | 127**              |                      |
|   |                       |                    | **n = 120**          |
+---+-----------------------+--------------------+----------------------+
| * |                       | 63 (49.6%)         | 60 (50%)             |
| * |                       |                    |                      |
| A |                       |                    |                      |
| n |                       |                    |                      |
| y |                       |                    |                      |
| B |                       |                    |                      |
| a |                       |                    |                      |
| s |                       |                    |                      |
| e |                       |                    |                      |
| l |                       |                    |                      |
| i |                       |                    |                      |
| n |                       |                    |                      |
| e |                       |                    |                      |
| P |                       |                    |                      |
| r |                       |                    |                      |
| e |                       |                    |                      |
| g |                       |                    |                      |
| n |                       |                    |                      |
| a |                       |                    |                      |
| n |                       |                    |                      |
| c |                       |                    |                      |
| y |                       |                    |                      |
| T |                       |                    |                      |
| e |                       |                    |                      |
| s |                       |                    |                      |
| t |                       |                    |                      |
| * |                       |                    |                      |
| * |                       |                    |                      |
+---+-----------------------+--------------------+----------------------+
|   | **[\>]{.underline} 2  | 18                 | 23                   |
|   | Baseline Tests**      |                    |                      |
+---+-----------------------+--------------------+----------------------+
| * |                       | 4 (3.2%)           | 2 (1.7%)             |
| * |                       |                    |                      |
| N |                       |                    |                      |
| o |                       |                    |                      |
| B |                       |                    |                      |
| a |                       |                    |                      |
| s |                       |                    |                      |
| e |                       |                    |                      |
| l |                       |                    |                      |
| i |                       |                    |                      |
| n |                       |                    |                      |
| e |                       |                    |                      |
| T |                       |                    |                      |
| e |                       |                    |                      |
| s |                       |                    |                      |
| t |                       |                    |                      |
| T |                       |                    |                      |
| a |                       |                    |                      |
| k |                       |                    |                      |
| e |                       |                    |                      |
| n |                       |                    |                      |
| * |                       |                    |                      |
| * |                       |                    |                      |
+---+-----------------------+--------------------+----------------------+
| * |                       | 60 (47.2%)         | 58 (48.3%)           |
| * |                       |                    |                      |
| N |                       |                    |                      |
| o |                       |                    |                      |
| t |                       |                    |                      |
| R |                       |                    |                      |
| e |                       |                    |                      |
| p |                       |                    |                      |
| o |                       |                    |                      |
| r |                       |                    |                      |
| t |                       |                    |                      |
| e |                       |                    |                      |
| d |                       |                    |                      |
| * |                       |                    |                      |
| * |                       |                    |                      |
+---+-----------------------+--------------------+----------------------+

Sixty-three (49.6%) Pre-RMP and 60 (50%) Post-RMP cases reported having
at least one baseline pregnancy test before starting isotretinoin
therapy. For those cases reporting baseline pregnancy testing, we found
that slightly more than one-quarter (29%, 18/63) of the Pre-RMP cases,
and more than one-third (38%, 23/60) of the Post-RMP cases reported at
least two baseline pregnancy tests.

Four Pre-RMP cases (3.2%, 4/127)) and two (1.7%, 2/120) Post-RMP cases
reported having no baseline pregnancy testing performed and 60 (47.2%,
60/127) Pre-RMP and 58 (48.3%, 58/120) Post-RMP cases did not report
whether or not baseline pregnancy testing had been performed.

**2.2 Pregnancy Testing During Isotretinoin Therapy**

The isotretinoin product label requires a pregnancy test each month
prior to the female patient receiving an isotretinoin prescription.

An evaluation of compliance with pregnancy testing during isotretinoin
treatment was performed. A comparison Pre-RMP data with Post-RMP data
was made.

  ------------------------------------------------------------------------
  **Table 11. Pregnancy Testing During                        
  Isotretinoin Therapy**                                      
  ----------------------------------------------- ----------- ------------
                                                  **Pre-RMP n **Post-RMP n
                                                  = 127**     = 120**

  **At Least One Pregnancy Test During            45 (35.4%)  47 (39.1%)
  Isotretinoin Therapy**                                      

  **No Pregnancy Test During Isotretinoin         4 (3.2%)    2 (1.7%)
  Therapy**                                                   

  **Pregnancy Testing Not Reported**              78 (61.4%)  71 (59.2%)
  ------------------------------------------------------------------------

-   Overall, 45 (35.4%) Pre-RMP cases and 47 (39.1%) Post-RMP cases
    reported at least one pregnancy test during isotretinoin use.

-   Four (3.2%) Pre-RMP and 2 (1.7%) Post-RMP cases reported having no
    pregnancy testing during isotretinoin therapy.

-   Additionally, 78 Pre-RMP (61.4%) cases and 71 (59.2%) Post-RMP cases
    did not report whether or not any pregnancy testing occurred during
    isotretinoin therapy. Of note 31 cases overall reported using
    isotretinoin for less than 30 days and may not have been eligible
    for pregnancy testing during treatment.

    **3. SUMMARY OF PATIENTS WHO BECAME PREGNANT PRIOR TO STARTING
    ISOTRETINOIN**

    **3.1 Baseline Pregnancy Testing**

A careful examination of the cases involving the 20 women who were
pregnant prior to starting therapy with isotretinoin was performed.
Sixteen of the 20 women reportedly received some pregnancy testing. The
other four cases did not mention whether baseline pregnancy testing was
conducted.

Of the 16 women who reportedly received baseline pregnancy testing, nine
reported two or more baseline pregnancy tests, six reported "a" baseline
pregnancy test, and the number of baseline tests was unknown in one
case. The results of the pregnancy tests were negative in eight patients
and positive in three. The results were unknown in the remaining five
patients.

The following describe the circumstances of the three with positive
pregnancy results:

-   One patient had two negative tests at the doctor's office and a
    subsequent home pregnancy test that was positive two weeks later and
    the day she initiated isotretinoin. She had taken only one dose
    (Post-RMP case).

-   A 32 year old female had her LMP September 17. On October 23 a blood
    pregnancy test was performed. The following day she commenced
    isotretinoin but stopped after one pill when she found out she was
    pregnant (Pre-RMP case).

-   A 33 year old female had her LMP June 3. She reportedly had
    irregular menstrual cycles. On July 26 a blood pregnancy test was
    performed. The following day she commenced isotretinoin. The
    pregnancy test was found to be positive, but according to the
    patient, was overlooked by the nurse. She had taken approximately 14
    capsules and discontinued isotretinoin when another test was
    positive (Pre-RMP case).

    **3.2 Compliance with Label Recommendations**

An evaluation of the isotretinoin treatment start date in relation to
first day of the last menstrual period (LMP) and baseline pregnancy
testing among patients who were pregnant prior to initiating therapy
with isotretinoin was performed. The product label states that the
second test (a confirmation test) should be done during the first 5 days
of the menstrual period immediately preceding the beginning of
isotretinoin therapy. Sixteen of the 20 cases provided LMP dates.

+-------+------+---------+---------+-----------------+---------------+
| **    |      |         |         |                 |               |
| Table |      |         |         |                 |               |
| 12.   |      |         |         |                 |               |
| LMP,  |      |         |         |                 |               |
| Bas   |      |         |         |                 |               |
| eline |      |         |         |                 |               |
| Preg  |      |         |         |                 |               |
| nancy |      |         |         |                 |               |
| (BL   |      |         |         |                 |               |
| Preg) |      |         |         |                 |               |
| Tes   |      |         |         |                 |               |
| ting, |      |         |         |                 |               |
| and   |      |         |         |                 |               |
| Is    |      |         |         |                 |               |
| otret |      |         |         |                 |               |
| inoin |      |         |         |                 |               |
| Start |      |         |         |                 |               |
| dates |      |         |         |                 |               |
| among |      |         |         |                 |               |
| 20    |      |         |         |                 |               |
| pat   |      |         |         |                 |               |
| ients |      |         |         |                 |               |
| al    |      |         |         |                 |               |
| ready |      |         |         |                 |               |
| pre   |      |         |         |                 |               |
| gnant |      |         |         |                 |               |
| prior |      |         |         |                 |               |
| to    |      |         |         |                 |               |
| initi |      |         |         |                 |               |
| ating |      |         |         |                 |               |
| isot  |      |         |         |                 |               |
| retin |      |         |         |                 |               |
| oin** |      |         |         |                 |               |
+-------+------+---------+---------+-----------------+---------------+
| Pre   | LMP  | BL Preg | Isotr   | Days b/n BL     | Days b/n LMP  |
| /Post |      |         | etinoin | Preg Test and   | and           |
| RMP   |      | test    | start   | isotretinoin    | isotretinoin  |
|       |      | date\*  | date    | start           | start         |
+-------+------+---------+---------+-----------------+---------------+
| Pre   | NR   | Oct 1   | Oct 1   | 0               | Unable to     |
|       |      |         |         |                 | determine     |
+-------+------+---------+---------+-----------------+---------------+
| Pre   | NR   | Aug 10  | Aug 10  | 0               | Unable to     |
|       |      |         |         |                 | determine     |
+-------+------+---------+---------+-----------------+---------------+
| Pre   | Jan  | NR      | Mar 5   | Unable to       | 46            |
|       | 18   |         |         | determine       |               |
+-------+------+---------+---------+-----------------+---------------+
| Pre   | Feb  | NR      | Mar 15  | Unable to       | 35            |
|       | 8    |         |         | determine       |               |
+-------+------+---------+---------+-----------------+---------------+
| Pre   | Mar  | Feb 13  | Feb 27  | 14              | NA^§^         |
|       | 5    |         |         |                 |               |
+-------+------+---------+---------+-----------------+---------------+
| Pre   | Mar  | NR      | Apr 1   | Unable to       | 23            |
|       | 8    |         |         | determine       |               |
+-------+------+---------+---------+-----------------+---------------+
| Pre   | Apr  | NR      | Jul 27  | Unable to       | 98            |
|       | 20   |         |         | determine       |               |
+-------+------+---------+---------+-----------------+---------------+
| Pre   | Jun  | Jul 26  | Jul 27  | 1               | 54            |
|       | 3    |         |         |                 |               |
+-------+------+---------+---------+-----------------+---------------+
| Pre   | Jul  | May 16  | Jul 31  | 76              | 25            |
|       | 6    |         |         |                 |               |
+-------+------+---------+---------+-----------------+---------------+
| Pre   | Aug  | Aug 30  | Sep 4   | 5               | 17            |
|       | 18   |         |         |                 |               |
+-------+------+---------+---------+-----------------+---------------+
| Pre   | Aug  | Sep 7   | Sep 17  | 10              | 27            |
|       | 20   |         |         |                 |               |
+-------+------+---------+---------+-----------------+---------------+
| Pre   | Sep  | Oct 23  | Oct 24  | 1               | 37            |
|       | 17   |         |         |                 |               |
+-------+------+---------+---------+-----------------+---------------+
| Post  | NR   | Dec 15  | Dec 15  | 0               | Unable to     |
|       |      |         |         |                 | determine     |
+-------+------+---------+---------+-----------------+---------------+
| Post  | Jan  | NR      | Feb 3   | Unable to       | 32            |
|       | 2    |         |         | determine       |               |
+-------+------+---------+---------+-----------------+---------------+
| Post  | Feb  | in Jan  | Feb 25  | 30+             | 21            |
|       | 4    |         |         |                 |               |
+-------+------+---------+---------+-----------------+---------------+
| Post  | Feb  | Feb 7   | Feb 20  | 13              | 15            |
|       | 5    |         |         |                 |               |
+-------+------+---------+---------+-----------------+---------------+
| Post  | Mar  | NR      | Apr 23  | Unable to       | 26            |
|       | 28   |         |         | determine       |               |
+-------+------+---------+---------+-----------------+---------------+
| Post  | Sep  | Sep 25  | Sep 30  | 5               | 19            |
|       | 11   |         |         |                 |               |
+-------+------+---------+---------+-----------------+---------------+
| Post  | Dec  | Dec 29  | Jan 15  | 17              | 22            |
|       | 24   |         |         |                 |               |
+-------+------+---------+---------+-----------------+---------------+
| Unk   | NR   | NR      | NR      | Unable to       | Unable to     |
|       |      |         |         | determine       | determine     |
+-------+------+---------+---------+-----------------+---------------+
| \*    |      |         |         |                 |               |
| Date  |      |         |         |                 |               |
| is    |      |         |         |                 |               |
| based |      |         |         |                 |               |
| on    |      |         |         |                 |               |
| co    |      |         |         |                 |               |
| nfirm |      |         |         |                 |               |
| atory |      |         |         |                 |               |
| or    |      |         |         |                 |               |
| only  |      |         |         |                 |               |
| bas   |      |         |         |                 |               |
| eline |      |         |         |                 |               |
| preg  |      |         |         |                 |               |
| nancy |      |         |         |                 |               |
| test  |      |         |         |                 |               |
| repo  |      |         |         |                 |               |
| rted; |      |         |         |                 |               |
| in    |      |         |         |                 |               |
| four  |      |         |         |                 |               |
| women |      |         |         |                 |               |
| dates |      |         |         |                 |               |
| for   |      |         |         |                 |               |
| the   |      |         |         |                 |               |
| bas   |      |         |         |                 |               |
| eline |      |         |         |                 |               |
| preg  |      |         |         |                 |               |
| nancy |      |         |         |                 |               |
| te    |      |         |         |                 |               |
| sting |      |         |         |                 |               |
| was   |      |         |         |                 |               |
| not   |      |         |         |                 |               |
| prov  |      |         |         |                 |               |
| ided. |      |         |         |                 |               |
|       |      |         |         |                 |               |
| §     |      |         |         |                 |               |
| pa    |      |         |         |                 |               |
| tient |      |         |         |                 |               |
| had   |      |         |         |                 |               |
| m     |      |         |         |                 |               |
| enses |      |         |         |                 |               |
| d     |      |         |         |                 |               |
| uring |      |         |         |                 |               |
| preg  |      |         |         |                 |               |
| nancy |      |         |         |                 |               |
+-------+------+---------+---------+-----------------+---------------+

Only two reported a baseline pregnancy test during the LMP, both during
the Post-RMP period. Seven of the 20 patients began isotretinoin therapy
within 5 days of the baseline pregnancy test, however not in conjunction
with the LMP. Moreover, none of the 16 patients (with an LMP date
reported) started isotretinoin within two weeks of their LMP. Although
the label does not instruct to start within a specified period of time
around the LMP, it does state that the baseline pregnancy test should be
conducted during the first five days of menses immediately preceding
isotretinoin therapy, and that the prescription for isotretinoin should
be dispensed within 7 days of the "qualification date" or confirmatory
pregnancy test. It is perhaps the lack of specific instructions that may
be a source of confusion to both practitioners as well as patients.

**4. CONTRACEPTIVE USE**

**4.1 Contraceptive Use during Isotretinoin Therapy**

Isotretinoin's product label requires that female patients commit to two
forms of effective birth control, at least one of which must be a
primary form, unless absolute abstinence is chosen, or the patient has
undergone a hysterectomy.

An evaluation of contraceptive use by patients reporting isotretinoin
associated pregnancies was performed. A comparison of Pre-RMP data with
Post-RMP data was made.

+-------------------------+---------------------+----------------------+
| **Table 13.             |                     |                      |
| Contraceptive Use with  |                     |                      |
| Isotretinoin**          |                     |                      |
+=========================+=====================+======================+
|                         | **Pre-RMP**         | **Post-RMP**         |
|                         |                     |                      |
|                         | **n = 127**         | **n = 120**          |
+-------------------------+---------------------+----------------------+
| **Any Birth Control     | 68 (53.5%)          | 70 (58.3%)           |
| Method**                |                     |                      |
+-------------------------+---------------------+----------------------+
| -   **One Method        | 50                  | 61                   |
|     (any)**             |                     |                      |
|                         | \(44\)              | \(54\)               |
| > **(One Method -       |                     |                      |
| > primary**[^5]**)**    |                     |                      |
+-------------------------+---------------------+----------------------+
| -   **Two Methods       | 18                  | 9                    |
|     (any)**             |                     |                      |
|                         | \(14\)              | \(7\)                |
| > **(Two methods -- 1   |                     |                      |
| > primary)**            |                     |                      |
+-------------------------+---------------------+----------------------+
| **No Birth Control      | 15 (11.8%)          | 6 (5%)               |
| Used/abstinence**       |                     |                      |
+-------------------------+---------------------+----------------------+
| **Not Reported**        | 44 (34.6%)          | 44 (36.7%)           |
+-------------------------+---------------------+----------------------+

The percentage of patients reporting any contraceptive use was about the
same Pre-RMP and Post-RMP; however the percentage reporting no
contraceptive use decreased during the Post-RMP year (11.8% and 5% for
Pre-RMP and Post-RMP cases, respectively).

Of those reporting any contraceptive use, the following was noted:

-   The majority of Pre-RMP cases (73.5%; 50/68) and Post-RMP cases
    (87.1%; 61/70) reported using one method of birth control during
    isotretinoin therapy.

    -   When one method of birth control was used, the majority of both
        Pre-RMP (88%; 44/50) and Post-RMP (88.5%; 54/61) cases used a
        primary method of contraception.

    -   A small number of Post-RMP cases (2/61) reported using the
        "morning after pill".

-   Of those cases reporting contraceptive use, 18 (26.5%) Pre-RMP
    cases, and nine (12.9%) Post-RMP cases reported using two methods of
    contraception.

    -   When two methods were used by either group, the majority
        (Pre-RMP - 14, Post-RMP - 7) reported using at least one primary
        method of contraception.

    -   A small number of Pre-RMP (4) and Post-RMP (2) cases used two
        secondary[^6] methods of contraception, instead of one primary
        and one secondary as described in the product label.

-   Hormonal contraception (oral or injection) was the most common
    method of contraception used in the Pre-RMP (48) and Post-RMP (55)
    cases.

Forty-four cases each (Pre-RMP 34.6%, Post-RMP 36.7%) did not report
whether or not contraception was used during the time of isotretinoin
use.

**4.2 Contraceptive Compliance during Isotretinoin Therapy**

Of the patients reporting contraceptive use, there were 32 Pre-RMP and
35 Post-RMP cases that provided information concerning contraceptive
compliance during isotretinoin therapy. The majority of cases (82.1%;
23/28 Pre-RMP, and 80%; 28/35 Post-RMP) reported non-compliance with
their chosen contraceptive methods. Five cases in each category reported
contraceptive failure. There were two Post-RMP cases reporting both
contraceptive failure and non-compliance.

  ---------------------------------- ------------------ ------------------
  **Table 14. Contraceptive                             
  Compliance**                                          

                                     **Pre-RMP**        **Post-RMP**

  **Any Compliance Statement**       28                 35

  **Non-compliant**                  23                 28

  **Contraceptive Failure**          5                  5

  **Contraceptive Failure *and*      \-\-\-\--          2
  non-compliant**                                       
  ---------------------------------- ------------------ ------------------

Non-compliance refers to patients that discontinued use of contraceptive
methods prior to label recommendations (during use and 30 days following
isotretinoin discontinuation), or those that missed doses or otherwise
inconsistently used contraceptive methods. Contraceptive failure is
defined as those patients that reported "contraceptive failure". Some
examples of contraceptive failure included:

-   Broken condoms

-   Decreases in oral contraceptive effectiveness due to interacting
    medications (oral antibiotics, carbamazepine)

-   Tubal ligation failure (procedure performed more than 10 years
    before estimated conception date)

    **5. OUTCOME DATA**

Both pregnancy outcome and fetal outcome data for all 325 cases was
tallied. Although these data are stratified by RMP period, any
enhancements to the Isotretinoin RMP are unlikely to affect the
pregnancy or fetal outcomes during these two periods.

**5.1 Pregnancy Outcomes**

The table below provides a summary of the pregnancy outcomes by RMP
category.

+-------------------------------+--------+--------+--------+--------+
| **Table 15. Pregnancy         |        |        |        |        |
| Outcomes**                    |        |        |        |        |
+===============================+========+========+========+========+
|                               | P      | Po     | U      | Total  |
|                               | re-RMP | st-RMP | nknown |        |
|                               |        |        |        | (      |
|                               | (      | (      | (n=78) | n=325) |
|                               | n=127) | n=120) |        |        |
+-------------------------------+--------+--------+--------+--------+
| Delivery                      | 18     | 7      | 4      | 29     |
+-------------------------------+--------+--------+--------+--------+
| Spontaneous abortion/ectopic  | 15     | 6      | 2      | 23     |
| pregnancy                     |        |        |        |        |
+-------------------------------+--------+--------+--------+--------+
| Elective Abortion             | 47     | 48     | 18     | 113    |
+-------------------------------+--------+--------+--------+--------+
| Unknown (lost to FU,          | 47     | 59     | 54     | 160    |
| pregnancy ongoing)            | (37%)  | (49%)  | (69%)  | (49%)  |
+-------------------------------+--------+--------+--------+--------+

The outcome of the pregnancy is unknown in almost half of all pregnancy
cases (160/325). As would be expected, this percentage is higher in the
unknown and in the Post-RMP cases where outcomes may not yet have
occurred been reported. About 35% of patients in the series elected to
terminate their pregnancy. Nine percent (29/325) of patients delivered a
live born infant.

The table below provides a breakdown of the 165 known pregnancy outcomes
by time of isotretinoin exposure.

  ------------------------------- ------------- --------------- -------------
  **Table 16. Pregnancy Outcome                                 
  by time of isotretinoin                                       
  exposure**                                                    

                                  Delivery      SAB/ectopic\*   Elective
                                                                Abortion

  **After discontinuation**                                     

  15 to 30 days                   10            2               5

  7 to 14 days                    3             2               5

  \< 7 days                       1             1               3

  **During isotretinoin**                                       

  \< 7 days                       5             4               5

  7 to 14 days                    4             3               14

  15 to 30 days                   2             2               29

  \> 30 days                      1             5               11

  Number of days exposed unknown  3             4               41

  Total                           29            23              113

  \*Spontaneous abortion and                                    
  ectopic pregnancies                                           
  ------------------------------- ------------- --------------- -------------

It appears that the longer the patient was exposed to isotretinoin
following conception, the greater the tendency of the patient to
terminate the pregnancy.

**5.2 Fetal Outcomes**

Twenty-nine patients reported delivery of a liveborn infant. Twenty
reported normal babies (at time of reporting) of which four were born
prematurely (2 to 5 weeks). Another mother had premature labor that was
successfully stopped. In another case a mother with a history of
epilepsy experienced seizure activity during pregnancy. Her pregnancy
was further complicated by polyhydraminos, cord entanglement, small
subchorionic hemorrhage, and decreased fetal movement but she
subsequently delivered a normal baby. There was also another infant in
whom a septal defect was noted in utero. Following birth, the infant
underwent echocardiography which ruled out a defect.

Seven reported some type of abnormality and the fetal outcome in the
remaining two was unknown. The mothers in three of the seven infants
with an abnormality discontinued isotretinoin 15 to 25 days prior to
conceiving. One infant developed gastroschisis and undescended testicles
both events that required surgery. The other was a male infant who
developed bilateral hydrocele and moulding of the anterior fontanel. In
the third, an ultrasound in utero showed a small spot on the fetal
heart. The mother delivered a female infant but no follow-up regarding a
possible cardiac anomaly was provided.

The mothers in the remaining four infants that developed an abnormality
conceived during isotretinoin therapy. Anomalies of the heart were
reported in two cases, kidney in one case, and facial anomalies and
retardation in one case. All four cases are briefly summarized below.

-   A male infant was born with hypoplastic left heart syndrome. His
    mother had taken isotretinoin for Darier's disease and was on her
    third month of isotretinoin when she conceived and reportedly used
    contraception inconsistently (oral contraceptives and condoms). She
    discontinued isotretinoin about two weeks after conception. The
    infant underwent open heart surgery and was eventually discharged
    from the hospital. (PostRMP case)

-   A female patient discontinued isostretinoin and her oral
    contraceptive about 3 weeks prior to conception, however took a
    single 40mg dose about 12 days after conception. An ultrasound
    examination at approximately 20 weeks gestation showed an atrial
    septal defect but normal valve movement over the foramen ovale. The
    mother gave birth to a female infant that was felt by the physician
    to be healthy. No additional followup information regarding the
    possible atrial septal defect was provided. (PreRMP case)

-   A female patient discontinued treatment with isotretinoin about a
    month after conception. According to the reporter, the female
    patient had been on isotretinoin for over two years and had not
    undergone any pregnancy or other laboratory tests while receiving
    isotretinoin. Her pregnancy was complicated by premature
    contractions at 29 weeks and polyhydraminos. She delivered a male
    infant at 38 weeks with hydronephrosis. The infant was evaluated by
    an urologist who stated that a scan showed bilateral megaureters
    that were non-refluxing and did not appear to be obstructed. Renal
    function was 64% on the left and 36% of the right with sluggish
    drainage. The plan at the time of consultation was follow-up with
    repeat renal scan. (PreRMP case)

-   This case was reported by a journalist who describes a female
    patient who became pregnant during the use of isotretinoin and
    subsequently delivered a baby with facial anomalies and retardation.
    It was not clear exactly when or how long the exposure to
    isotretinoin had occurred. (Unknown case)

The patterns of isotretinoin embryopathy are characteristic
malformations involving craniofacial, cardiac, thymic, and central
nervous system structures. The malformations include microtia/anotia,
micrognathia, cleft palate, conotruncal heart defects and aortic-arch
abnormalities, thymic defects, retinal or optic-nerve abnormalities, and
central nervous system malformations.[^7] Cognitive deficits in more
than half the children exposed in utero have also been reported in
follow-up studies to 5 years of age.[^8]

**[DISCUSSION]{.underline}**

The data for these analyses are primarily based on spontaneous reporting
to passive surveillance systems such as AERS and are subject to
reporting bias. It is possible for instance, that there was an increase
in the reporting of pregnancies in the Post-RMP year, due to publicity
around the implementation of the RMP. Additionally spontaneous reports
are variable in quality and completeness; as such, lack of information
does not necessarily indicate lack of compliance with the RMP.
Furthermore, experience of pregnancy failures may not represent general
experience of isotretinoin users.

Although there were no prespecified metrics agreed upon regarding any of
these data, experience from pregnancy failures may help guide future RMP
efforts to further reduce pregnancy exposures.

Review of the pregnancy exposure data comparing the Pre-RMP to the
Post-RMP period can by summarized as follows:

-   One hundred twenty-seven (127) pregnancy exposures occurred during
    the Pre-RMP year and 120 cases occurred during the Post-RMP year.
    These numbers do not reflect an appreciable decrease in pregnancies
    with the enhanced RMP and may in fact reflect an increase relative
    to the overall decline in use of isotretinoin in the year following
    the implementation of the RMP.

-   The number of women who were already pregnant prior to initiating
    therapy with isotretinoin were 12 Pre-RMP and 7 Post-RMP.

-   Pregnancies occurred throughout isotretinoin treatment for both
    Pre-RMP and Post-RMP periods. Although more pregnancies occurred
    during the first month of isotretinoin use compared to most other
    months (15-19%), the aggregate number of pregnancies that occurred
    after the first month of isotretinoin therapy was greater
    (\~42-53%).

-   The number of days of exposure to isotretinoin following conception
    has not changed between the Pre-RMP or Post-RMP periods.

-   There has been no improvement in baseline pregnancy testing (49.6%
    and 50% for Pre-RMP and Post-RMP, respectively) and only a slight
    improvement in monthly pregnancy testing (35.4% and 39.1% for
    Pre-RMP and Post-RMP, respectively) and in the use of at least one
    method of birth control (53.5% and 58.3% for Pre-RMP and Post-RMP,
    respectively) among patients who became pregnant during the Pre-RMP
    period versus the Post-RMP period.

Although the actual reason that the pregnancies occurred could not be
delineated from the cases in the series, some common themes were
identified and could account for the pregnancy failures. These are
summarized below:

-   Twenty-one women were not using any form of contraception when the
    exposed pregnancy occurred or chose abstinence as a means of
    contraception and then went on to engage in unprotected sexual
    intercourse.

-   The majority of women describe using only one method of birth
    control. Only 15% of women reporting birth control information
    reported use of "appropriate" birth control consisting of two
    methods, at least one of which was a primary method.

-   Fifty-one of 138 women (38%) who reported using at least one form of
    contraception reported non-compliance with their chosen method of
    contraception. Non-compliant women either discontinued use of
    contraception early, missed doses of their oral contraceptive, or
    used contraception inconsistently.

-   An evaluation of isotretinoin treatment start dates in relation to
    first day of the last menstrual period (LMP) and baseline pregnancy
    testing among 16 of 20 patients who were pregnant prior to
    initiating therapy with isotretinoin was performed.

    -   Only two reported a baseline pregnancy test during the LMP.

    -   None of the 16 patients started isotretinoin within two weeks of
        their LMP. Although the label does not instruct to start within
        a specified period of time around the LMP, it does state that
        the baseline pregnancy test should be conducted during the first
        five days of menses immediately preceding isotretinoin therapy,
        and that the prescription for isotretinoin should be dispensed
        within 7 days of the "qualification date" or confirmatory
        pregnancy test

-   Seven women took isotretinoin without medical supervision. In five,
    the patients saved isotretinoin and restarted for an acne flare, one
    obtained isotretinoin at a swap meet, and one obtained a
    prescription in January but did not take until December of the same
    year.

The outcome of the pregnancy is unknown in almost half of all the
pregnancy cases reviewed. As would be expected, this percentage is
higher in the Post-RMP cases where outcomes may not yet have occurred or
been reported. Sixty-seven percent (113/160) of those that reported
pregnancy outcome information elected to terminate the pregnancy. Nine
percent (29/325) of patients delivered a live born infant and a small
number of these cases reported a congenital anomaly.

**[CONCLUSION]{.underline}**

The number of pregnancy exposures has not decreased appreciably and may
have increased relative to the overall decrease in use of isotretinoin
in the year following the implementation of the enhanced Isotretinoin
Risk Management Program. Our review of a number of parameters comparing
the Pre-RMP to the Post-RMP suggest minimal or no improvement with the
implementation of the RMP. However, it should be emphasized that
pre-specified metrics were not defined and that experience of pregnancy
failures may not represent general experience of isotretinoin users.

[^1]: See Isotretinoin Utilization Review, pg 30.

[^2]: Source: Adverse Event Reporting System, Request for Information --
    Roche Submission: September 18, 2003, Ranbaxy Submission: November
    18, 2003, and Genpharm Submission: November 17, 2003.

[^3]: Hoffmann-La Roche submission--General Correspondence*: 1 Year
    Report on the SMART Program*, June 30, 2003

[^4]: See Isotretinoin Utilization Review, pg 30.

[^5]: Primary methods of contraception: oral contraceptives, implantable
    hormones, injectable hormones, hormonal patch, intrauterine devices,
    hormonal vaginal contraceptive ring, sterilization (male, female)

[^6]: Secondary methods of contraception: diaphragms, latex condoms,
    cervical cap,

[^7]: Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Broun JT, et al.
    Retinoic acid embryopathy. N Engl J Med 1985; 313:837-41.

[^8]: Teratology Society. Recommendations for isotretinoin use in women
    of childbearing potential. Teratology 1991;44:1-6.