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| ######          | **DEPARTMENT OF HEALTH AND HUMAN SERVICES**        |
|  **MEMORANDUM** |                                                    |
|                 | **PUBLIC HEALTH SERVICE**                          |
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|                 | ######### FOOD AND DRUG ADMINISTRATION             |
|                 |                                                    |
|                 | **CENTER FOR DRUG EVALUATION AND RESEARCH**        |
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Date: January 29, 2004

To: Steven K. Galson, M.D., M.P.H

> Acting Director, Center for Drug Evaluation and Research

From: Paul Seligman, M.D., M.P.H.

> Acting Director, Office of Drug Safety

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

> Deputy Director, Office of Drug Safety

Subject: Overview of the 1^st^ Year of the Isotretinoin Risk Management
Program (RMP)

The attached Office of Drug Safety (ODS) review evaluates the impact of
the enhanced post-marketing risk management program for isotretinoin
since its implementation in April 2002. The review consists of four
reports that address the following the topics:

Pregnancy exposures and contraceptive use patterns

Drug utilization patterns

Implementation of the pharmacy sticker program

Surveys of patient-reported compliance and outcomes

Summarized in this overview are the key findings of each report.

# Pregnancy exposures

For the one-year period prior to the implementation of the risk
management program (pre-RMP), 127 women with pregnancy exposures to
isotretinoin were reported. For a comparable one-year period subsequent
to its implementation (post-RMP) 120 such cases were reported.
Prescriptions for isotretinoin declined during the post-RMP period (see
below.)

In the pre-RMP period, 12 women were pregnant prior to the initiation of
the therapy and 7 women in the post-RMP period; one pregnancy could not
be dated precisely. The remaining pregnancies occurred following the
initiation of therapy and were observed throughout the course of
treatment both pre- and post-RMP. Incomplete or absent patient adherence
to labeled birth control recommendations was observed among the
pregnancy cases, including no contraceptive use, use of only one method
of contraception, or non-compliance with the chosen method of birth
control. When patients were pregnant prior to starting isotretinoin,
labeled recommendations for baseline pregnancy testing and initiation of
use timed with menses were not followed in certain cases. Seven reported
pregnancies occurred in women who took isotretinoin without medical
supervision.

**Drug utilization**

The number of isotretinoin prescriptions dispensed declined 23% in the
first year following the implementation of the enhanced program from
1.51 million to 1.16 million. Refill prescriptions decreased from 16% in
the pre-RMP year to 2.4% in the post-RMP year.

**Pharmacy sticker compliance survey**

Surveys of pharmacies to determine compliance with the prescription
sticker element of the risk management program found that the number of
prescriptions filled used the qualification sticker consistently
exceeded the primary objective of 90%. The survey had important
limitations including a low pharmacy response rate and the failure of
some large pharmacy chains to participate.

**Patient surveys**

> Participation rates in patient surveys were 16-19% during the pre-RMP
> period compared to 22-26% post-RMP. Survey respondents differed in
> their age distribution and prescriber specialty profile from all
> females receiving isotretinoin prescriptions. These findings raise
> questions about the representativeness of survey respondents for all
> isotretinoin users.
>
> For those participants assumed to be fertile^1^ and sexually active
> (\"at risk for pregnancy\"), 91% reported at least one pregnancy test
> prior to initiation of therapy whereas 68% reported receiving two
> pregnancy tests prior to therapy. For the year prior to this enhanced
> risk management program, among sexually active women inferred to be
> fertile^1^, 74% reported having received pregnancy testing prior to
> initiation of therapy.

Concerning the use of qualification stickers, 92% of survey participants
reported receiving a prescription with a qualification sticker, in close
agreement with the pharmacy sticker compliance survey results. Among
survey participants who reported receiving a prescription with a
qualification sticker, 9% reported they did [not]{.underline} have a
pregnancy test.

Regarding the use of birth control among sexually active women aged
15-45 years inferred to be fertile^1^, 4.2% reported they did not use
any means of birth control. Conversely, 95.8% used some form of birth
control early in their isotretinoin treatment course; 46% used two forms
of birth control of which one was considered primary.

^1^Fertile was defined by ages greater than or equal to 15 years and
less than or equal to 45 years, having an intact uterus, and being
premenopausal.

**Conclusion**

Notwithstanding widespread use of the isotretinoin sticker by pharmacy
and patient surveys, pregnancies on isotretinoin therapy continue to be
reported in equivalent numbers to the preRMP period. Pregnancy testing
at least once at the initiation of therapy improved postRMP, with
performance of two tests ranging from 63 to 68% of survey respondents
depending on the at-risk denominator used. Women who reported
pregnancies to FDA indicated some level of confusion about the
appropriate timing of pregnancy testing relative to menses and the
initiation of therapy, possibly due to ambiguity in the labeled
directions.

Only one year has passed since the implementation of enhanced efforts to
manage the pregnancy risks of isotretinoin. The limited and incomplete
data reported to date indicate that compliance with sticker use and
refill restrictions is high, but that the absolute linkage of stickers
with pregnancy testing is incomplete. According to patient surveys,
contraceptive practices have improved, but high-risk behaviors around
contraception (such as improper use or lack of use) continue to place a
portion of women at risk of an isotretinoin-exposed pregnancy.