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iPledge: Fetal exposure to isotretinoin continues

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Fetal exposure to isotretinoin still persists ‘at unacceptable levels’

The rate of fetal exposure to isotretinoin has generally decreased since the implementation of the iPledge program, but rates have plateaued since 2011, and it is unclear why the exposure rate does not continue to decrease, Arielle R. Nagler, MD, wrote in a related editorial.

As noted by Tkachenko et al., it is not possible to infer that iPledge resulted in declines in fetal exposure, abortions, and pregnancy-related complications. Use of long-acting reversible contraception, education about contraception use, and reporting fatigue could be factors in the decline, Dr. Nagler noted. “The inability to clearly demonstrate causality, combined with the unexplained delay and plateau in the number of fetal exposures to isotretinoin after the implementation of iPledge, makes it difficult to draw firm conclusions about the role of iPledge in this reported trend,” she said.

The decrease in fetal exposure could also potentially be explained by effects of iPledge on the availability of isotretinoin for women of childbearing age. Indeed, studies have shown a significant decrease in isotretinoin prescriptions in this patient population after iPledge was implemented.

Despite lack of data, there is still too much fetal exposure to isotretinoin, wrote Dr. Nagler, which calls into question the efficacy of the iPledge program. “We can all agree that 1 fetal exposure to isotretinoin should be too many, but without taking isotretinoin off the market, we will never achieve zero fetal exposures to isotretinoin. Still, we can – and should – expect more from a REMS [Risk Evaluation and Mitigation Strategy] program,” Dr. Nagler concluded.

Dr. Nagler is with the department of dermatology at New York University. She reported no relevant conflicts of interest.


 

FROM JAMA DERMATOLOGY

The number of pregnancies among women taking isotretinoin has decreased since the introduction of the iPledge program, but pregnancy, abortions, and fetal defects associated with isotretinoin exposure are still occurring in women of reproductive age, according to a retrospective study published in JAMA Dermatology.

In 2006, the Food and Drug Administration implemented the iPledge program, with requirements that include women of childbearing age having a negative pregnancy test and evidence of using two forms of contraception monthly to use isotretinoin, a teratogen. “Although the number of pregnancy-related adverse events for patients taking isotretinoin has decreased since 2006, pregnancies, abortions, and fetal defects associated with isotretinoin exposure continue to be a problem,” Elizabeth Tkachenko, BS, from the University of Massachusetts Medical School, Worcester, and coauthors concluded. “Further research is required to determine the most efficacious system to reduce complications for patients and administrative requirements for physicians while at the same time maintaining access to this important drug.” (iPledge followed other Risk Evaluation and Mitigation Strategy systems for isotretinoin.)

She and her colleagues performed a retrospective evaluation of pregnancy-related adverse events related to isotretinoin that had occurred between January 1997 and December 2017 using the FDA Adverse Event Reporting System (FAERS), which receives reports from prescribers, consumers, and pharmaceutical manufacturers. While there could be many different classification terms for each individual, any number of adverse events reported by an individual was counted as one pregnancy. Ms. Tkachenko and colleagues classified abortions, pregnancies during contraception use, and pregnancy-related defects into separate subgroups for analysis.

From 1997 to 2017, there were 6,740 pregnancies among women (mean age, 24.6 years) during treatment with isotretinoin reported to FAERS, with 7 reports in 1997, and a peak of 768 pregnancies in 2006. Almost 70% (4,647) of the pregnancies were reported after iPledge was introduced. Between 2011 and 2017, there were 218-310 pregnancy reports each year.

Of the total number of pregnancy reports during the study period, 1,896 were abortions (28.1% of the total); 10.9% of the total number of pregnancy reports were spontaneous abortions (733). The number of abortions peaked in 2008, with 291 reports, of which 85% were therapeutic abortions. Also peaking in 2008 was the number of reports of pregnancies while taking a contraceptive (64). After 2008, pregnancies and abortions dropped.

Fetal defects peaked in 2000, with 34 cases reported, and dropped to four or fewer reports annually after 2008.

“Our findings demonstrate that reports of pregnancy among women taking isotretinoin are concentrated among those aged 20 to 29 years, peaked in 2006, and have been consistent since 2011,” the authors wrote.

Limitations of the study, they noted, include limitations of FAERS data and possible reporting fatigue among doctors and patients. The total number of isotretinoin courses prescribed to this patient population is also unknown, which affected their ability to determine the true rate of pregnancy-related adverse events, they noted.

The other authors for this study were from Harvard Medical School and the departments of dermatology at Brigham and Women’s Hospital, both in Boston, as well as the University of Pennsylvania, Philadelphia. One author reported support from an award by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health and salary support from a Pfizer Fellowship in Dermatology Patient Oriented Research grant to the trustees of the University of Pennsylvania. The other authors reported no relevant conflicts of interest.

SOURCE: Tkachenko E et al. JAMA Dermatol. 2019. doi: 10.1001/jamadermatol.2019.1388.

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