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Isotretinoin (Accutane®) Exposure
During Pregnancy
January 2006
What is Accutane®?
 Accutane® is the brand name for the compound
isotretinoin (an oral medication).
 In 2002, isotretinoin became available for use as
a generic. Other brand names include Claravis,
Amnesteem and Sotret.
 Isotretinoin is one of several types of retinoids –
a synthetic form of vitamin A.
FDA Guidelines: Indications for Usage
• Isotretinoin is used to treat a type of severe acne
(nodular acne) that has not been helped by other
treatments, including antibiotics.
• Isotretinoin helps restore the normal function of the
skin follicles and lowers production of sebum (oil).
However, isotretinoin is sometimes used/prescribed for
conditions other than this approved indication, such as
for milder acne.
Severe Cystic Acne
Accutane® Capsules
NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.
Source: Physician’s Desk Reference. www.drugs.com/PDR/Accutane_Capsules.html
Vitamin A, Retinoic Acid & Isotretinoin
Definitions
• Vitamin A: A fat-soluble vitamin necessary for bodily
processes such as normal fetal development, skin
renewal and vision
• Retinoid: Natural or synthetic derivative of vitamin A
• Retinoic Acid: A synthetic form of vitamin A
–Isotretinoin (Accutane®) is a retinoic acid.
Vitamin A
• The body can make vitamin A from precursors such as
beta carotene.
• Most of the vitamin A we consume is from preformed
vitamin A, which includes those from food (e.g., dairy
products & liver) and some vitamin supplements.
• Vitamin supplements that contain beta carotene do not
pose a risk for excess vitamin A exposure, but some
vitamin supplements do contain preformed vitamin A
(retinol).
Vitamin A (cont.)
• Pregnant women should make sure that any multivitamin or
prenatal supplement contains no more than the Daily Value
(DV) of preformed vitamin A (see below).
• Appropriate dose of Vitamin A
– The Institute of Medicine daily Recommended Dietary Allowance
(RDA) is 2,333 International Units (IU) for women, and 3,000 IU
for men.
– The labels on foods and supplements use an older set of FDA
daily requirements called the "Daily Values (DV)," which includes
5,000 IU of vitamin A.
Adverse Effects of Vitamin A & Retinoids
• If taken during pregnancy, isotretinoin and other retinoids can
be teratogenic (can cause birth defects).
• Vitamin A is an essential nutrient, but too much vitamin A can
also have adverse effects similar to retinoids.
– 10,000 IU or more of maternal retinol intake from supplements is
associated with an increased risk for cardiac defects.1
1. Rothman KJ et al. NEJM 1995;333:1365-73 & Botto LD et al. Epidemiology 2001;12:491-6.
Chemical Structures of
(a) Vitamin A
(b) Isotretinoin
a) Vitamin A is formed by carboxylation of the aldehyde group (OH).
b) Isotretinoin is also called 13-cis retinoic acid.
Retinoids (Retinoic Acids) in the
Developing Fetus/Embryo
 Retinoids (including retinoic acids such as
isotretinoin) play an important role in the
development of an embryo—both a deficiency or
excess can interfere with normal development.
 Retinoids are involved in signaling the correct
patterning of structures formed very early in
embryonic development, including the pharyngeal
(or branchial) arches.
Source: Recommendations for Isotretinoin Use in Women of Childbearing Potential. Teratology 1991;44:1-6.
Pharyngeal (Branchial) Arches
Forms during the
4th week of
embryologic
development.
Source: http://isc.temple.edu/marino/embryology/parch98/parchdev.htm
Isotretinoin Embryopathy
Synonyms:
 Accutane® Embryopathy
 Accutane®, Fetal Effects of
 Retinoic Acid Embryopathy
 Isotretinoin, Fetal Effects of
 Isotretinoin Teratogen Syndrome
 Fetal Retinoid Syndrome
Isotretinoin Embryopathy (cont.)
• Craniofacial alterations
– Absent or abnormal ears
– Cleft palate
– Small jaw
• Central nervous system abnormalities
– Neural tube defects
– Poor cognitive performance (reduced IQ)
• Cardiovascular malformations
• Kidney alterations
• Thymic aplasia
Source: Jones KL. Smith’s Recognizable Patterns of Human Malformation, 5th Ed. London: W.B. Saunders, 1996.
Teratogenic Effects of Isotretinoin
• Miscarriage
• Growth delays before and after birth (prenatal and
postnatal growth retardation)
• Cognitive impairments
– Fifty percent of affected children have an IQ below
85 (average intelligence being an IQ of 110-100).
Source: Adams J, Lammer EJ. Reprod Toxicol 1993;7:175-7 & Jones KL. Smith’s Recognizable Patterns of Human Malformation, 5th Ed. London:
W.B. Saunders, 1996.
Isotretinoin Embryopathy
Source: Jones KL. Smith’s Recognizable Patterns of Human Malformation, 5th Ed. London: W.B. Saunders, 1996.
Isotretinoin Embryopathy
Source: Jones KL. Smith’s Recognizable Patterns of Human Malformation, 5th Ed. London: W.B. Saunders, 1996.
Isotretinoin - Elimination from the Body
How long does isotretinoin stay in the body?
• The average elimination half-life (the time it takes for
the body to eliminate one-half of the drug) of
isotretinoin is 21 hours (with a a standard deviation 8.2
hours). However, the elimination half-life of some of its
breakdown products is up to 50 hours.
• Therefore, most of isotretinoin and its byproducts
should be gone within 10 days of the last dose.
Sources: Reprotox® (Isotretinoin), Physicians’ Desk Reference 2005.
Isotretinoin & Pregnancy
How long should a woman wait to become pregnant
after discontinuing isotretinoin treatment?
• The manufacturer’s female patient consent form states
that women should not get pregnant one month prior to
treatment, during treatment AND for one month after
stopping treatment with isotretinoin.
• 2 separate forms of contraception are required at the
same time during the period of time stated above.
Source: Physicians’ Desk Reference 2005.
Brief History of Isotretinoin (Accutane®)
Isotretinoin (Accutane®)* Use in the United States
• Since 1982, about 5 million patients have been treated
in the U.S. and 12 million worldwide (as of 2000).1
• Retail pharmacies dispensed 19.8 million outpatient
prescriptions for isotretinoin (Accutane®) between
1982 and 2000.2
• Between 1992 and 2000, the number of prescriptions
increased rapidly to almost 2 million in 2000—a 250%
increase.2
* Isotretinoin refers to Accutane® in all of the above, since the patent for Accutane ® did not expire until 2002.
1. Ellison E. Presentation from Hoffman-LaRoche at the FDA Dermatologic and Ophthalmic Advisory Committee meeting. September 18-19, 2000.
2. Wysowski DK et al. J Am Acad Dermatol 2002;46:505-9.
FDA Approval of Accutane®
• FDA approved Accutane® in 1982.
• At the time of approval, Accutane® received a
pregnancy risk rating of X (category X).
Category X = Adequate, well-controlled studies
in animals or pregnant women have
demonstrated positive evidence of fetal
abnormalities.
No indication for usage when pregnant or
breastfeeding, should be avoided entirely.
Product needs to be labeled that it should be avoided
during pregnancy.
FDA Current Categories for Drug Use in Pregnancy www.fda.gov/fdac/features/2001/301_preg.html#categories
Isotretinoin (Accutane®) as a Human Teratogen
Shortly after FDA approval of Accutane®, case reports of
adverse pregnancy outcomes began to surface.
• April 1984-CDC MMWR
Weekly reported 29
case of “adverse
outcomes among
women taking
isotretinoin during the
first trimester of
pregnancy” reported to
the FDA and Roche
Laboratories
(manufacturer of
Accutane®).
Source: www.cdc.gov/mmwr/preview/mmwrhtml/00000310.htm
Pregnancy Prevention Program (PPP)
• 1988 - The Pregnancy Prevention Program (PPP) was
started by Roche to:
– further educate women and their physicians about the
dangers of using Accutane® (isotretinoin) during pregnancy
– ensure that prescriptions would only be given to women
with severe recalcitrant nodular acne who could comply
with contraceptive requirements, materials were distributed
to all dermatologists & nondermatologists identified as
prescribers
•
Guidelines for physicians (e.g., obtaining negative pregnancy tests,
warning patients of risks), patient qualification checklist, brochure for
patients, contraceptive information, and consent form.
Source: Mitchell AA et al. N Engl J Med 1995;333:101-6.
The Slone Survey - Survey Data
• Beginning in 1989, Roche sponsored a survey of women taking
Accutane® to assess compliance with the PPP.
• The Slone Epidemiology Unit at Boston University's School of
Public Health ran the survey.
• The survey set out to: track pregnancy rates and outcomes, assess
patients' awareness of risks, and patient & physician behavior.
• Physicians were encouraged, but not required to enroll patients.
• 40% or less of reproductive-aged women taking Accutane® were
estimated to have participated in this study.
Sources: MMWR Morb Mortal Wkly Rep 2000;49:28-31 & Mitchell AA et al. N Engl J Med 1995;333:101-6.
The Slone Survey - Results
• Of the ~ 500,000 women who voluntarily enrolled in
this survey from 1989 to 1999*:
– 1019 pregnancies occurred in women taking
isotretinoin.
• 887 resulted in terminations (either elective,
spontaneous or due to ectopic pregnancy).
• 117 resulted in live births.
• 15 patients had unknown outcomes.
* The Slone survey has estimated that 38% to 40% of reproductive-aged women taking Accutane® chose to
enroll in the survey
Source: Mitchell AA et al. Survey of Accutane in Women. Briefing Materials for the FDA Dermatologic & Opthalmic Drugs Advisory Committee Meeting on Sept.
18-19, 2000. Available online at: www.fda.gov/ohrms/dockets/ac/00/backgrd/3639b1.htm
The Slone Survey - Results
• Of the 117 live births, medical records were
obtained for 63 infants.
• 8 had major malformations (craniofacial anomalies,
deafness, cardiac malformation).
• 11 had minor malformations (ear anomalies,
Mongolian spots, bilateral inguinal hernias, mild
developmental delay).
Source: Mitchell AA et al. Survey of Accutane in Women. Briefing Materials for the FDA Dermatologic & Opthalmic Drugs Advisory Committee Meeting on Sept.
18-19, 2000. Available online at: www.fda.gov/ohrms/dockets/ac/00/backgrd/3639b1.htm
Pregnancy Prevention Program (PPP) - Summary
• Since Accutane®'s approval, Roche has received
close to 2,000 reports of Accutane®-exposed
pregnancies.
• 70 percent of exposures occurred after the PPP
began.
• More stringent measures were needed to prevent
exposure in reproductive-aged women taking
Accutane®.
Source: Meadows M. The Power of Accutane: The Benefits and Risks of a Breakthrough Acne Drug. U.S. Food and Drug Administration, FDA Consumer
Magazine. March-April, 2001.
System to Manage Accutane® Related
Teratogenicity (SMART)
• Began in 2002
• Voluntary registration and survey program
• Prescribing physicians read a booklet and sign a
letter of understanding. They are then given yellow
stickers to affix to prescriptions.
• The yellow sticker signifies that the physician has
appropriately counseled the patient, including
assuring that the patient meets all criteria and has
signed informed consent.
Source: Roche Pharmaceuticals. New Prescribing Procedures for Accutane as of April 10, 2002.
SMART Requirements
• Two negative urine or serum pregnancy tests
before starting Accutane®
• Two reliable forms of contraception for at least one
month before taking Accutane®, during treatment,
and for one month after discontinuing Accutane®,
even when one of the forms of contraception is
hormonal
• Only receive a 30 day supply of medication, with
refills contingent upon repeat (monthly) negative
pregnancy tests
Source: System to Manage Accutane Related Teratogenicity (S.M.A.R.T.)™ Guide to Best Practices. Roche Pharmaceuticals.
Available online at www.fda.gov/cder/drug/infopage/accutane/default.htm
Accutane® blister pack with the “avoid pregnancy” warning icons
March of Dimes Advocacy &
Recent Developments
FDA Meeting - February 2004
• The March of Dimes has been advocating for a “single,
stringently monitored and restricted system for clinical use of
isotretinoin, modeled after the system currently used for
thalidomide” since 2000.
• In February 2004, the FDA convened a meeting of the Drug
Safety and Risk Management & the Dermatologic and Opthalmic
Drug Advisory Committees to discuss:
– The effectiveness of the SMART program
– To consider changes to the current isotretinoin risk
management plan (riskMAP)
• The March of Dimes made a statement, reinforcing the
recommendation for a single registry system as well as the
development of a plan for restricting online sales of isotretinoin.
Letter to The Wall Street Journal from
March of Dimes President Dr. Jennifer L. Howse
February 26, 2004
Potent Acne Medicine Can Cause Birth Defects
“The target market is primarily young adults, of whom
half are women of reproductive age. The tragic
consequences for pregnant users are isotretinoinexposed pregnancies that result in entirely
preventable major birth defects and miscarriages.
The FDA must step up its oversight. We have
recommended the agency require a single, stringently
monitored and restricted program for isotretinoin,
such as the highly effective system created for
thalidomide in 1998.”
What a Single Registry System
Would Look Like
• Only physicians registered with the program may
dispense isotretinoin.
• Pharmacists must be registered with the program to
dispense isotretinoin.
• Patients must comply with mandatory education,
contraception and monitoring measures.
• Pregnancy testing must be performed both before and
during treatment.
• Only a one-month supply is dispensed at a time.
2004 FDA Developments
In November 2004, the FDA announced plans to make the
following changes to their isotretinoin risk management
program:
• New program would be modeled after the successful national
program for preventing pregnancy exposures to thalidomide.
• Single registration–requires registration with one centralized
clearinghouse (prescribers, dispensing pharmacies & patients
must each register)
• All manufacturers (brand name or generic) must participate in
the same registry
Source: FDA Talk Paper. FDA Announces Enhancement to Isotretinoin Risk Management Program. November 23, 2004. Available
online at www.fda.gov/cder/drug/infopage/accutane/accutane_historical.htm
2004 FDA Developments
For female patients capable of becoming pregnant, this
single registry will:
–Initally confirm the appropriately-timed & documented negative
pregnancy test before authorizing dispensing of a prescription for
isotretinoin.
–Monitor that informed consent, counseling and patient education
have occurred.
–Ensure ongoing education and that repeated negative pregnancy
tests will occur monthly for subsequent prescriptions.
Source: FDA Talk Paper. FDA Announces Enhancement to Isotretinoin Risk Management Program. November 23, 2004. Available
online at www.fda.gov/bbs/topics/ANSWERS/2004/ANS01328.html
Update - Latest FDA Developments
In August 2005, the FDA announced the approval of a new
national, mandatory, single-registry system called iPLEDGE
Wholesalers, manufacturers, prescribers (doctors) &
patients are all required to register in a national computerbased database:
1) via internet at www.ipledgeprogram.com
OR
2) by telephone at 1-866-495-0654
Sources: FDA News. FDA Announces Strengthened Risk Management Program to Enhance Safe Use of Isotretinoin (Accutane) for Treating Sever Acne. Available online at
www.fda.gov/bbs/topics/NEWS/2005/NEW01218.html, Accutane (isotretinoin) Q&A. Available online at: www.fda.gov/cder/drug/infopage/accutane/accutane_QA20050812.htm &
Isotretinoin (marketed as Accutane) Capsule Information. Available online at www.fda.gov/cder/drug/infopage/accutane/default.htm
Update - Latest FDA Developments (cont.)
Program details:
Requirements for women of childbearing age include:
• Must not be pregnant or breastfeeding
• Two negative pregnancy tests before initial prescription
• Monthly pregnancy tests before each refill
• Use of two forms of birth control or abstain from intercourse one month prior,
during & one month after treatment
• Sign a Patient Information/Informed Consent form that contains warnings about
the potential risks of taking isotretinoin.
Pharmacists must check the database before filling prescriptions for isotretinoin to
ensure that women have fulfilled the requirements
For full details, see FDA Accutane (isotretinoin) Q&A at: www.fda.gov/cder/drug/infopage/accutane/accutane_QA20050812.htm
Sources: FDA News. FDA Announces Strengthened Risk Management Program to Enhance Safe Use of Isotretinoin (Accutane) for Treating Sever Acne. Available online at
www.fda.gov/bbs/topics/NEWS/2005/NEW01218.html & Accutane (isotretinoin) Q&A. Available online at: www.fda.gov/cder/drug/infopage/accutane/accutane_QA20050812.htm
Update - Latest FDA Developments (cont.)
Program details (cont.):
• Manufacturers participating in iPLEDGE include:
•
•
•
•
Hoffman-LaRoche (Accutane®)
Genpharm (Amnesteem, distributed by Mylan/Bertek)
Ranbaxy Pharmaceuticals (Sotret)
Barr Laboratories (Claravis)
• The FDA & manufacturers (listed above) will work together to implement
and evaluate the program
• All pregnancy exposures to isotretinoin must be reported to the FDA
(MedWatch, 1-800-FDA-1088) & to the iPLEDGE pregnancy registry
More information is available on the Isotretinoin (Accutane®) section of the FDA
Web site: www.fda.gov/cder/drug/infopage/accutane/default.htm
Sources: FDA News. FDA Announces Strengthened Risk Management Program to Enhance Safe Use of Isotretinoin (Accutane) for Treating Sever Acne. Available online at
www.fda.gov/bbs/topics/NEWS/2005/NEW01218.html & Accutane (isotretinoin) Q&A. Available online at: www.fda.gov/cder/drug/infopage/accutane/accutane_QA20050812.htm
March of Dimes
Position on Retinoids/Isotretinoin (Accutane®)
No woman should begin oral retinoid treatment if she
is or may be pregnant, and no woman should
become pregnant during oral retinoid treatment.
• Link between use in pregnancy and serious birth
defects: Isotretinoin is a potent teratogen.
• The FDA should diligently monitor effectiveness of the
new mandatory risk management plan and report
findings of pregnancy exposures or system failures in
a timely way.
Ongoing Concerns-Internet Sales
• Buying isotretinoin over the Internet
– Bypass safety mechanisms
– No patient education
• Currently little oversight on Internet sales of isotretinoin
– Accutane® is on the FDA Import Alert drug list, which alerts FDA field
personnel to the possible importation of these drugs, provides guidance
as to their detention and refusal of admission into the United States.
– The FDA has issued consumer safety alerts warning the public to not
buy Accutane® over the Internet.
– Since 1999, the FDA has been implementing an Internet Drug Sales
Action Plan in order to minimize the dangers of purchasing drugs online.
Source: FDA Web site. Accutane (Isotretinoin) www.fda.gov/cder/drug/infopage/accutane/default.htm
Accessed August 2005
Challenges: Global nature of the Internet makes online sales of drugs difficult to regulate.
– Sales of drugs to U.S. residents from foreign Web sites
– Anonymity of product source
– Overlap of state, Federal and international jurisdiction
Source: FDA Web site. Internet Drug Sales www.fda.gov/ola/2004/internetdrugs0318.html
Ongoing Concerns-Generic Forms
• The patent on Accutane® expired in 2002, allowing
other drug companies to make & sell isotretinoin.
• Additional generic forms of isotretinoin now
available include: Claravis, Amnesteem, Sotret.
• Patients might not realize that they are the same
as Accutane®, with the same risks.
Ongoing Concerns-Proper Usage
• Prescribing Accutane® (isotretinoin) for less severe
acne
– One study1 looking at trends in use of isotretinoin in the U.S.
found the proportion of isotretinoin use for mild and moderate
acne increased, while the proportion for severe acne declined
between 1993 and 2000.
• Underappreciation of the risks
What Price Beauty Boston Globe Magazine 4/27/2003
“My skin glows when I’m using it. I would die if they took it off the market.”
“Today, nearly three out of 1,000 women between the ages of 15 and 44
are Accutane users.”
1. Wysowski DK et al. J Am Acad Dermatol 2002;46:505-9.
Resources on the Web
U.S. Food & Drug Administration (FDA)
Accutane® (Isotretinoin)
www.fda.gov/cder/drug/infopage/accutane/default.htm
Organization of Teratology Information Specialists (OTIS)
Teratology Information Specialists (TIS) provide comprehensive and multidisciplinary
resources for medical consultation on prenatal exposures.
OTIS Web site: www.otispregnancy.org/
National Toll-Free Number: 866-626-OTIS (866-626-6847)
Fact Sheet on Accutane® (isotretinoin):
www.otispregnancy.org/otis_fact_sheets.asp
March of Dimes
Accutane® and Other Retinoids:
www.marchofdimes.com/professionals/681_1168.asp
Acknowledgements
We would like to thank the Education Committee
of the Organization of Teratology Information Specialists
(OTIS) for their review and contribution.
Isotretinoin (Accutane®) Exposure
During Pregnancy
Thank You!!!