+--------------------+-------------------------------------------------+
| **M E M O R A N D  | **DEPARTMENT OF HEALTH AND HUMAN SERVICES       |
| U M**              | 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: Gerald Dal Pan, M.D., M.H.S., Director

Office of Drug Safety

Division of Surveillance, Research, and Communication Support HFD-410

FROM: Aaron B. Mendelsohn, Ph.D., M.P.H. Epidemiologist

Laura Governale, Pharm.D., Drug Use Specialist

Office of Drug Safety

Division of Surveillance, Research, and Communication Support HFD-410

SUBJECT: PID D030417

Drug: Isotretinoin

> Topic: Isotretinoin Utilization

::: Definition-Term
**[EXECUTIVE SUMMARY]{.underline}**
:::

This consult describes utilization and prescribing patterns for
isotretinoin in the year prior to (1 April 2001 -- 31 March 2002), and
the year following (1 April 2002 -- 31 March 2003), implementation of
the System to Manage Accutane-Related Teratogenicity**™** (SMART**™**),
a risk management plan developed by Hoffmann-La Roche to minimize the
risk of pregnancy among women taking Accutane®. Using proprietary data
sources available to the Office of Drug Safety, we found similar results
to the utilization data analyses reported by Hoffmann-LaRoche. We note
that the number of isotretinoin prescriptions declined roughly 23% in
the year following SMART compared to the previous year, suggesting that
the SMART program may have influenced the number of isotretinoin
prescriptions dispensed. Refill prescriptions also declined from 16.0%
(n=238,000) of all isotretinoin prescriptions in the year before SMART
to 2.4% (n=28,000) in the post-SMART year.

SMART appeared to have had little impact on other utilization variables
such as prescribing physician specialty and patient age and gender. In
the year prior to SMART, 76% of the prescriptions dispensed were written
by dermatologists, similar to the proportion in the 12 months following
SMART (80%). Females accounted for approximately one-half of the
isotretinoin claims in both the pre- and post-SMART eras. The majority
of isotretinoin claims were from persons aged 16-29 years who accounted
for 58.5% of the isotretinoin prescription claims in the year before
SMART, and 59.5% of the prescriptions in the year following SMART.

**[METHODS]{.underline}**

We examined IMS Health's National Prescription Audit *Plus*™ (NPA) for
the total number of prescriptions (including refills) and prescriber
specialty for all isotretinoin products since April 2001. NPA measures
the retail dispensing of prescriptions, or the frequency with which
drugs move out of retail pharmacies (including chain, independent, food
store, mail order, discount houses, mass merchandiser, and long-term
care pharmacies) into the hands of consumers via formal prescriptions.
NPA provides national estimates of dispensed prescriptions based upon
data from 22,000 U.S. pharmacies accounting for approximately 45% of all
prescriptions in the U.S**.**

To describe the gender and age distribution of patients dispensed
isotretinoin products, we examined data from AdvancePCS™, a large
pharmacy benefits manager (PBM) for the time period of April 2001
through March 2003, inclusive. AdvancePCS currently manages prescription
benefits for over 50 million patient lives and processing for over 300
million prescription claims annually for patients with prescription drug
insurance coverage. The data are not nationally projected, and their
representativeness of the U.S. population is not known.

**[RESULTS]{.underline}**

In the 12-months prior to SMART (1 April 2001 -- 31 March 2002),
1,508,000 prescriptions were dispensed for isotretinoin (Table 1). The
number of isotretinoin prescriptions dispensed declined approximately
23% to 1,160,000 prescriptions in the first year following the
implementation of the SMART program. Of the approximately 1.5 million
isotretinoin prescriptions dispensed in the year before SMART, 16.0%
(n=238,000) were refill prescriptions, compared to 2.4% (n=28,000) in
the post-SMART year.

Generic versions of isotretinoin penetrated the market in the last
quarter of calendar year 2002 (i.e., after SMART), accounting for 3.8%
of the total isotretinoin prescriptions dispensed (Figure 1). Since the
end of 2002, the use of generic isotretinoin products has been on the
rise, with generics representing 33.2%, 46.7%, and 49.5% of the
prescriptions dispensed in the first, second, and third quarters of
2003, respectively.

Dermatologists were the most common prescribers of isotretinoin,
accounting for roughly three-quarters of prescriptions dispensed. The
SMART program did not appear to have an effect on the distribution of
isotretinoin prescribers specialities. In the year prior to SMART, 76%
of the prescriptions dispensed were written by dermatologists, similar
to the proportion in the 12 months following SMART (80%).

Isotretinoin use remains nearly evenly distributed between male and
female patients. According to data from AdvancePCS, females accounted
for 50.4% of the claims for isotretinoin in the year before SMART and
49.2% of the claims in the year post-SMART.

The age distributions for isotretinoin users were similar in the pre-
and post-SMART eras (Table 2). Among female patients, isotretinoin use
was most common in persons aged 16-29 years, with this age group
accounting for 58.5% of the isotretinoin prescription claims in the year
before SMART, and 59.5% of the prescriptions in the year following
SMART.

+----------------------+----------------------+-----------------------+
| **Table 1.           |                      |                       |
| Utilization of       |                      |                       |
| Isotretinoin in the  |                      |                       |
| United States in the |                      |                       |
| Year Preceding and   |                      |                       |
| Following            |                      |                       |
| Implementation of    |                      |                       |
| the SMART Program**  |                      |                       |
+----------------------+----------------------+-----------------------+
|                      | **Pre-SMART**        | **Post-SMART**        |
|                      |                      |                       |
|                      | (1 Apr 01 -- 31 Mar  | (1 Apr 02 -- 31 Mar   |
|                      | 02)                  | 03)                   |
+----------------------+----------------------+-----------------------+
| \# of Prescriptions  | 1,508,000            | 1,160,000             |
| Dispensed^a^         |                      |                       |
+----------------------+----------------------+-----------------------+
| n (%) Refills^a^     | 238,000 (15.6)       | 28,000 (2.4)          |
+----------------------+----------------------+-----------------------+
| n (%) Generic^a,b^   | 0 (0)                | 119,000 (10.3)        |
+----------------------+----------------------+-----------------------+
| n (%) Prescriptions  | 1,073,000 (76.1)^d^  | 881,000 (79.9)^d^     |
| Written by           |                      |                       |
| Dermatologists^a^    |                      |                       |
+----------------------+----------------------+-----------------------+
| \% Female^c^         | 50.4%                | 49.2%                 |
+----------------------+----------------------+-----------------------+
| a US Data Source:    |                      |                       |
| IMS Health, IMS      |                      |                       |
| National             |                      |                       |
| Prescription Audit   |                      |                       |
| Plus™, for 4/01 to   |                      |                       |
| 3/02; accessed 03    |                      |                       |
| December 2003.       |                      |                       |
|                      |                      |                       |
| b Generic version of |                      |                       |
| isotretinoin became  |                      |                       |
| available in the     |                      |                       |
| last quarter of      |                      |                       |
| calendar year 2002   |                      |                       |
|                      |                      |                       |
| c Advance PCS™       |                      |                       |
| Dimension Rx,        |                      |                       |
| accessed 11 December |                      |                       |
| 2003                 |                      |                       |
|                      |                      |                       |
| d Based upon         |                      |                       |
| 1,410,000 and        |                      |                       |
| 1,103,000 Rx's       |                      |                       |
| dispensed,           |                      |                       |
| respectively, as     |                      |                       |
| prescriber           |                      |                       |
| information was      |                      |                       |
| sometimes unknown or |                      |                       |
| missing              |                      |                       |
+----------------------+----------------------+-----------------------+

+----------------------+------+------+------+-------+-------+-------+
| **Table 2. Age       |      |      |      |       |       |       |
| Distribution of      |      |      |      |       |       |       |
| Patients with        |      |      |      |       |       |       |
| Isotretinoin Claims  |      |      |      |       |       |       |
| in the United States |      |      |      |       |       |       |
| in the Year          |      |      |      |       |       |       |
| Preceding and        |      |      |      |       |       |       |
| Following            |      |      |      |       |       |       |
| Implementation of    |      |      |      |       |       |       |
| the SMART            |      |      |      |       |       |       |
| Program^\*^**        |      |      |      |       |       |       |
+----------------------+------+------+------+-------+-------+-------+
| Age Group (years)    | *    |      |      |       |       |       |
|                      | *Per |      |      |       |       |       |
|                      | cent |      |      |       |       |       |
|                      | of   |      |      |       |       |       |
|                      | Pati |      |      |       |       |       |
|                      | ents |      |      |       |       |       |
|                      | By   |      |      |       |       |       |
|                      | Age  |      |      |       |       |       |
|                      | Gro  |      |      |       |       |       |
|                      | up** |      |      |       |       |       |
+----------------------+------+------+------+-------+-------+-------+
|                      | *    |      |      | **Po  |       |       |
|                      | *Pre |      |      | st-SM |       |       |
|                      | -SMA |      |      | ART** |       |       |
|                      | RT** |      |      |       |       |       |
|                      |      |      |      | (1    |       |       |
|                      | (1   |      |      | Apr   |       |       |
|                      | Apr  |      |      | 02 -- |       |       |
|                      | 01   |      |      | 31    |       |       |
|                      | --   |      |      | Mar   |       |       |
|                      | 31   |      |      | 03)   |       |       |
|                      | Mar  |      |      |       |       |       |
|                      | 02)  |      |      |       |       |       |
+----------------------+------+------+------+-------+-------+-------+
|                      | All  | Fem  | M    | All   | F     | Males |
|                      | Pati | ales | ales | Pat   | emale | Only  |
|                      | ents | Only | Only | ients | sOnly | (%)   |
|                      | (%)  | (%)  | (%)  | (%)   | (%)   |       |
+----------------------+------+------+------+-------+-------+-------+
| 1-11                 | 0.4  | 0.5  | 0.3  | 0.3   | 0.3   | 0.2   |
+----------------------+------+------+------+-------+-------+-------+
| 12-15                | 19.8 | 13.9 | 25.7 | 20.6  | 14.7  | 26.3  |
+----------------------+------+------+------+-------+-------+-------+
| 16-19                | 36.4 | 26.1 | 46.7 | 37.9  | 27.5  | 47.9  |
+----------------------+------+------+------+-------+-------+-------+
| 20-29                | 22.1 | 28.7 | 15.4 | 21.6  | 28.3  | 15.1  |
+----------------------+------+------+------+-------+-------+-------+
| 30-39                | 11.8 | 17.7 | 5.8  | 10.5  | 16.4  | 4.7   |
+----------------------+------+------+------+-------+-------+-------+
| 40-44                | 3.9  | 5.9  | 1.9  | 3.8   | 5.6   | 2.0   |
+----------------------+------+------+------+-------+-------+-------+
| 45+                  | 5.7  | 7.2  | 4.2  | 5.4   | 7.1   | 3.8   |
+----------------------+------+------+------+-------+-------+-------+
| ^\*^Advance PCS™     |      |      |      |       |       |       |
| Dimension Rx,        |      |      |      |       |       |       |
| accessed 11 December |      |      |      |       |       |       |
| 2003                 |      |      |      |       |       |       |
+----------------------+------+------+------+-------+-------+-------+

::: Definition-Term
**[CONCLUSIONS]{.underline}**
:::

The number of isotretinoin prescriptions declined roughly 23% in the
year following SMART compared to the previous year, suggesting that the
SMART program may have influenced the number of isotretinoin
prescriptions dispensed. SMART appeared to have had little impact on
other utilization variables such as prescribing physician specialty and
patient age and gender.

![](media/image1.wmf){width="9.677777777777777in"
height="5.786111111111111in"}

[US Data Source]{.underline}: IMS Health, IMS National Prescription
Audit Plus, for 4/01 to 10/03; accessed: 03 December 2003

[Note]{.underline}: SMART was implemented 1 April 2002