Opinion
EDITORIAL
Isotretinoin and Pregnancy Prevention Do We Need to Take a Long, Hard Look at Ourselves? Emily M. Altman, MD
It’s no news that isotretinoin, the most effective treatment for severe or recalcitrant acne, is a potent teratogen. From its release as Accutane by Hoffman-LaRoche in 1982, isotretinoin had been classified as a pregnancy category X drug, defined as a drug Related article page 366 with positive evidence of human fetal risk, where the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. Risk management at the time of initial approval was limited to labeling, which described the risk of teratogenicity in the package insert and the patient information brochure. In relatively short order, it was clear that such labeling was not enough to reduce the risk of fetal exposure to isotretinoin. If one combines the teratogenic potential of isotretinoin and the fact that 50% of pregnancies in the United States are unplanned,1 preventing fetal exposure to isotretinoin becomes crucial. According to the US Food and Drug Administration (FDA) Drug Use Data, Accutane use in women increased more than 200% from 1992 to 1999.2 As of 1998, there were over 1.4 million isotretinoin prescriptions written in the United States.3 Half of the patients taking isotretinoin were women, and 85% to 90% of these women were of childbearing potential, ages 15 to 44 years. The first reports of birth defects secondary to isotretinoin appeared in 1983. By the 2000, there were 1995 fetal exposures to isotretinoin, which resulted in 1446 elective or spontaneous terminations and 383 live births, of which there were 162 infants with congenital anomalies. The future of our best weapon against a disease that hassuchphysicalandpsychologicalrepercussionswasprecarious. In 1988, a short article titled “The Needless Tragedies of Accutane” appeared in the New York Times Health Section.4 In it, the unnamed author claimed that 97% of those prescribed Accutane can be treated with other drugs and that the FDA failed to make sure that physicians do not overprescribe the drug. The author went on to say, “But the company (Hoffman-LaRoche), the FDA, and careless dermatologists share the blame for failing to minimize its side effects. Frank Young, the FDA’s commissioner, now has a clear remedial task: Regulate Accutane so that all who need it get it, with no birth defects.”4 The FDA regulations came. The first risk reduction program was the Accutane Pregnancy Prevention Program (PPP) in 1988, which proved to be unsuccessful in reducing pregnancy risk in patients prescribed Accutane, followed by the FDA’s System to Manage Accutane-Related Teratogenicity (SMART) in 2002. Both the PPP and SMART were initiated by Roche, the manufacturer of Accutane. Because the SMART program did not substantially change pregnancy rates in patients prescribed Accutane, the FDA instituted iPledge, its most restrictive risk reduction program, on jamadermatology.com
March 1, 2006.5 On July 30, 2007, the Associated Press6 reported that the number of pregnancies in the first year of iPledge was about the same as the numbers reported annually prior to FDA regulations. Unfortunately, what did decrease was the number of patients treated with isotretinoin. A study conducted to evaluate the impact of iPledge on isotretinoin fetal exposure in a large California multispecialty medical group showed that there was an overall 29% decrease in treatment courses and patients treated with isotretinoin after the implementation of iPledge.7 It seems that more and more stringent regulations, which were going to solve the problem of fetal exposure to isotretinoin, did not work. Where is the disconnect? The Drug Safety and Risk Management Advisory Committee’s iPledge year 1 update stated that the most common reasons for pregnancy during iPledge include contraceptive failure and noncompliance with birth control methods.8 Similarly, under SMART, the most commonly reported reasons for pregnancy during isotretinoin therapy were unsuccessful attempts at abstinence, use of ineffective contraception, inconsistent use of contraception, unexpected sexual activity, and contraceptive failure.9 Let’s look at these factors more closely. In 2003, Isaacs and Creinin10 examined the impact of prior health care provider counseling on previous use of contraception in women seeking surgical abortion. The study concluded that miscommunication between patients and their health care provider negatively affected the use of a primary contraceptive method in 14% of the patients. A study published in the Canadian Family Physician11 in 2006 looked at the self-reported reasons for women’s noncompliance with pregnancy prevention recommendations while receiving isotretinoin treatment. The study was designed to assess whether prescribing physicians advised female patients receiving isotretinoin according to pregnancy prevention recommendations, whether women understood those recommendations, and whether women complied with recommendations to prevent pregnancy. A standardized questionnaire was administered by telephone to 47 eligible female patients who were 14 years or older, were fertile as far as they knew, and were treated with isotretinoin at the time of the interview or in the preceding 6 months. The authors found that the association of women’s use of double contraception with their recollection that physicians discussed pregnancy prevention during the interview was statistically significant. They concluded that women’s retention of knowledge and their perception of the precautions taken by physicians are essential for their compliance. One additional patient in 3 will comply with double contraception when physicians discuss that issue. The absolute risk reduction was 37%. Another study,12 published in 2010, examined adherence to oral contraception by women taking category X medications. The JAMA Dermatology April 2014 Volume 150, Number 4
Copyright 2014 American Medical Association. All rights reserved.
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361
Opinion Editorial
study found that of the 146 758 women of childbearing age who received pregnancy category X medications, only 18% were prescribed oral contraception. These rates are similar to those of other women of childbearing age. Women who were prescribed both teratogenic medications and oral contraceptives demonstrated no better adherence than the overall population to other medication. Women who received statins were more adherent, but those prescribed antineoplastic, retinoids, or sedative hypnotic medications were less adherent. Adherence rates among women prescribed contraception by an obstetrician-gynecologist (OB-GYN) were similar to those of the total population. When the prescriber was a primary care provider, women were more likely to be adherent. Women prescribed oral contraception by a dermatologist were more likely to be nonadherent. Unfortunately, the reasons for such nonadherence were not specified. In their survey of 1472 women with no history of abortion, Biggs and Foster13 explored the possible reasons for nonadherence to contraception. They found that only 8% of women accurately estimated the risk of conception from engaging in 1 act of unprotected sex; 26% of the women correctly rated the effectiveness of condoms; and over half of the women correctly rated the effectiveness of oral and intrauterine contraception. The authors concluded that improving women’s knowledge of the effectiveness of various contraceptive methods may encourage more effective and consistent contraceptive use. In this issue, Werner et al14 present a small but important study of women’s experiences with isotretinoin risk reduction counseling. The authors interviewed 16 women who had used isotretinoin treatment to determine their perceptions of isotretinoin-associatedrisksandofwaystoavoidsuchrisks.Women clearly understood the teratogenic potential of isotretinoin but felt that their contraceptive counseling was incomplete and had ARTICLE INFORMATION Author Affiliation: Summit Medical Group, Berkeley Heights, New Jersey. Corresponding Author: Emily M. Altman, MD, Department of Dermatology, Summit Medical Group, One Diamond Hill Road, Lawrence Pavillion, Berkeley Heights, NJ 07922 ([email protected]). Published Online: November 20, 2013. doi:10.1001/jamadermatol.2013.6973.
/1988/05/12/opinion/the-needless-tragedies-of -accutane.html. Accessed August 15, 2013. 5. Pitts M, Karwoski C, Mendelsohn A; US Food and Drug Administration. Isotretinoin pregnancy exposure: spontaneous reports 1 year prior to, and 1 year after implementation of the current RMP: Joint Dermatologic and Ophthalmic Drugs and Drug Safety and Risk Management Advisory Committee Meeting, 2004.http://www.fda.gov/ohrms/dockets/ac/04/slides /4017S1_06_Pitts.ppt. Accessed August 15, 2013.
Conflict of Interest Disclosures: Dr Altman is a consultant to Ogilvy Health, an advertising agency that works with numerous dermatology-related products; however, none are related to this editorial.
6. NBC News online report by Associated Press, August 15, 2013. http://www.nbcnews.com/id /20041453/ns/health-pregnancy/t/some -accutaneusers-pregnant-despite-warning /#.UlknGFAkJ8E. Accessed August 15, 2013.
REFERENCES
7. Shin J, Cheetham TC, Wong L, et al. The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care system. J Am Acad Dermatol. 2011;65(6):1117-1125.
1. Henshaw SK. Unintended pregnancy in the United States. Fam Plann Perspect. 1998;30(1):24-29, 46. 2. US Food and Drug Administration. Accutane and pregnancy exposure. http://www.fda.gov/ohrms /dockets/ac/00/slides/3639s1c.pdf. Accessed August 15, 2013.
362
less understanding of effective contraceptive methods. The authors encourage clinicians to provide more information on the highly effective methods of contraception to help their female patients avoid fetal exposure to isotretinoin. In 2009, Kanelleas et al15 reported that none of the pregnancies that occurred in their patients during isotretinoin therapy could have been prevented by closer adherence to the guidelines of either the UK or US protocols. They suggested that parenteral progesterone only contraceptives, which are more than 99% effective and are independent of the patient’s individual compliance, be adopted as the standard approach to contraception for female patients considered for isotretinoin therapy. The idea that all women exposed to isotretinoin should use only contraception methods that are more than 99% effective in preventing pregnancy is a tempting one, because this would save much heartache to both the patients and their physicians. It is my opinion that providing all pros and cons of all available contraceptive methods and evaluating the patient’s non– isotretinoin-related risks in using such methods is outside the scope of a dermatology practice; however, it is definitely within the scope of our practice to provide clear information on the effectiveness and acceptable choices of various contraceptive methods and to refer our patients to knowledgeable OB-GYN colleagues for further evaluation and counseling. The message is loud and clear. If we want to retain the ability to use isotretinoin, an indispensable tool in our armamentarium, we have to find ways to increase adherence to contraceptive methods that will reduce and, hopefully, eliminate fetal exposure to isotretinoin. Yes, the responsibility for decreasing fetal exposure to isotretinoin lies on the shoulders of both the physician and the patient, but if we have avenues to improve on the numbers of pregnancies exposed to isotretinoin by better communication with our patients, we must take it.
3. Stern RS. Medication and medical service utilization for acne 1995-1998. J Am Acad Dermatol. 2000;43(6):1042-1048.
8. US Food and Drug Administration; Drug Safety and Risk Management Advisory Committee; Dermatologic and Ophthalmic Drugs Advisory Committee. Briefing document for iPledge year 1 update, 2007. http://www.fda.gov/ohrms/dockets /ac/07/briefing/2007-4311b1-02-ipledge.pdf. Accessed August 15, 2013.
4. The needless tragedies of Accutane. New York Times. May 12, 1988. http://www.nytimes.com
9. Perlman SE, Leach EE, Dominguez L, Ruszkowski AM, Rudy SJ. “Be smart, be safe, be
sure”: the revised Pregnancy Prevention Program for women on isotretinoin. J Reprod Med. 2001;46(2)(suppl):179-185. 10. Isaacs JN, Creinin MD. Miscommunication between healthcare providers and patients may result in unplanned pregnancies. Contraception. 2003;68(5):373-376. 11. Boucher N, Beaulac-Baillargeon L. Pregnancy prevention among women taking isotretinoin: failure to comply with the recommendations. Can Fam Physician. 2006;52:338-339. 12. Steinkellner A, Chen W, Denison SE. Adherence to oral contraception in women on Category X medications. Am J Med. 2010;123(10):929-934, e1. 13. Biggs MA, Foster DG. Misunderstanding the risk of conception from unprotected and protected sex. Women’s Health Issues. 2013;23(1):e47-e53. 14. Werner CA, Papic MJ, Ferris LK, et al. Women's experiences with isotretinoin risk reduction counseling [published online November 20, 2013]. JAMA Dermatol. doi:10.1001 /jamadermatol.2013.6862. 15. Kanelleas AI, Thornton S, Berth-Jones J. Suggestions for effective contraception in isotretinoin therapy. Br J Clin Pharmacol. 2009;67(1):137-138.
JAMA Dermatology April 2014 Volume 150, Number 4
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Georgetown University Medical Center User on 05/22/2015
jamadermatology.com
EDITORIAL
Isotretinoin and Pregnancy Prevention Do We Need to Take a Long, Hard Look at Ourselves? Emily M. Altman, MD
It’s no news that isotretinoin, the most effective treatment for severe or recalcitrant acne, is a potent teratogen. From its release as Accutane by Hoffman-LaRoche in 1982, isotretinoin had been classified as a pregnancy category X drug, defined as a drug Related article page 366 with positive evidence of human fetal risk, where the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. Risk management at the time of initial approval was limited to labeling, which described the risk of teratogenicity in the package insert and the patient information brochure. In relatively short order, it was clear that such labeling was not enough to reduce the risk of fetal exposure to isotretinoin. If one combines the teratogenic potential of isotretinoin and the fact that 50% of pregnancies in the United States are unplanned,1 preventing fetal exposure to isotretinoin becomes crucial. According to the US Food and Drug Administration (FDA) Drug Use Data, Accutane use in women increased more than 200% from 1992 to 1999.2 As of 1998, there were over 1.4 million isotretinoin prescriptions written in the United States.3 Half of the patients taking isotretinoin were women, and 85% to 90% of these women were of childbearing potential, ages 15 to 44 years. The first reports of birth defects secondary to isotretinoin appeared in 1983. By the 2000, there were 1995 fetal exposures to isotretinoin, which resulted in 1446 elective or spontaneous terminations and 383 live births, of which there were 162 infants with congenital anomalies. The future of our best weapon against a disease that hassuchphysicalandpsychologicalrepercussionswasprecarious. In 1988, a short article titled “The Needless Tragedies of Accutane” appeared in the New York Times Health Section.4 In it, the unnamed author claimed that 97% of those prescribed Accutane can be treated with other drugs and that the FDA failed to make sure that physicians do not overprescribe the drug. The author went on to say, “But the company (Hoffman-LaRoche), the FDA, and careless dermatologists share the blame for failing to minimize its side effects. Frank Young, the FDA’s commissioner, now has a clear remedial task: Regulate Accutane so that all who need it get it, with no birth defects.”4 The FDA regulations came. The first risk reduction program was the Accutane Pregnancy Prevention Program (PPP) in 1988, which proved to be unsuccessful in reducing pregnancy risk in patients prescribed Accutane, followed by the FDA’s System to Manage Accutane-Related Teratogenicity (SMART) in 2002. Both the PPP and SMART were initiated by Roche, the manufacturer of Accutane. Because the SMART program did not substantially change pregnancy rates in patients prescribed Accutane, the FDA instituted iPledge, its most restrictive risk reduction program, on jamadermatology.com
March 1, 2006.5 On July 30, 2007, the Associated Press6 reported that the number of pregnancies in the first year of iPledge was about the same as the numbers reported annually prior to FDA regulations. Unfortunately, what did decrease was the number of patients treated with isotretinoin. A study conducted to evaluate the impact of iPledge on isotretinoin fetal exposure in a large California multispecialty medical group showed that there was an overall 29% decrease in treatment courses and patients treated with isotretinoin after the implementation of iPledge.7 It seems that more and more stringent regulations, which were going to solve the problem of fetal exposure to isotretinoin, did not work. Where is the disconnect? The Drug Safety and Risk Management Advisory Committee’s iPledge year 1 update stated that the most common reasons for pregnancy during iPledge include contraceptive failure and noncompliance with birth control methods.8 Similarly, under SMART, the most commonly reported reasons for pregnancy during isotretinoin therapy were unsuccessful attempts at abstinence, use of ineffective contraception, inconsistent use of contraception, unexpected sexual activity, and contraceptive failure.9 Let’s look at these factors more closely. In 2003, Isaacs and Creinin10 examined the impact of prior health care provider counseling on previous use of contraception in women seeking surgical abortion. The study concluded that miscommunication between patients and their health care provider negatively affected the use of a primary contraceptive method in 14% of the patients. A study published in the Canadian Family Physician11 in 2006 looked at the self-reported reasons for women’s noncompliance with pregnancy prevention recommendations while receiving isotretinoin treatment. The study was designed to assess whether prescribing physicians advised female patients receiving isotretinoin according to pregnancy prevention recommendations, whether women understood those recommendations, and whether women complied with recommendations to prevent pregnancy. A standardized questionnaire was administered by telephone to 47 eligible female patients who were 14 years or older, were fertile as far as they knew, and were treated with isotretinoin at the time of the interview or in the preceding 6 months. The authors found that the association of women’s use of double contraception with their recollection that physicians discussed pregnancy prevention during the interview was statistically significant. They concluded that women’s retention of knowledge and their perception of the precautions taken by physicians are essential for their compliance. One additional patient in 3 will comply with double contraception when physicians discuss that issue. The absolute risk reduction was 37%. Another study,12 published in 2010, examined adherence to oral contraception by women taking category X medications. The JAMA Dermatology April 2014 Volume 150, Number 4
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Georgetown University Medical Center User on 05/22/2015
361
Opinion Editorial
study found that of the 146 758 women of childbearing age who received pregnancy category X medications, only 18% were prescribed oral contraception. These rates are similar to those of other women of childbearing age. Women who were prescribed both teratogenic medications and oral contraceptives demonstrated no better adherence than the overall population to other medication. Women who received statins were more adherent, but those prescribed antineoplastic, retinoids, or sedative hypnotic medications were less adherent. Adherence rates among women prescribed contraception by an obstetrician-gynecologist (OB-GYN) were similar to those of the total population. When the prescriber was a primary care provider, women were more likely to be adherent. Women prescribed oral contraception by a dermatologist were more likely to be nonadherent. Unfortunately, the reasons for such nonadherence were not specified. In their survey of 1472 women with no history of abortion, Biggs and Foster13 explored the possible reasons for nonadherence to contraception. They found that only 8% of women accurately estimated the risk of conception from engaging in 1 act of unprotected sex; 26% of the women correctly rated the effectiveness of condoms; and over half of the women correctly rated the effectiveness of oral and intrauterine contraception. The authors concluded that improving women’s knowledge of the effectiveness of various contraceptive methods may encourage more effective and consistent contraceptive use. In this issue, Werner et al14 present a small but important study of women’s experiences with isotretinoin risk reduction counseling. The authors interviewed 16 women who had used isotretinoin treatment to determine their perceptions of isotretinoin-associatedrisksandofwaystoavoidsuchrisks.Women clearly understood the teratogenic potential of isotretinoin but felt that their contraceptive counseling was incomplete and had ARTICLE INFORMATION Author Affiliation: Summit Medical Group, Berkeley Heights, New Jersey. Corresponding Author: Emily M. Altman, MD, Department of Dermatology, Summit Medical Group, One Diamond Hill Road, Lawrence Pavillion, Berkeley Heights, NJ 07922 ([email protected]). Published Online: November 20, 2013. doi:10.1001/jamadermatol.2013.6973.
/1988/05/12/opinion/the-needless-tragedies-of -accutane.html. Accessed August 15, 2013. 5. Pitts M, Karwoski C, Mendelsohn A; US Food and Drug Administration. Isotretinoin pregnancy exposure: spontaneous reports 1 year prior to, and 1 year after implementation of the current RMP: Joint Dermatologic and Ophthalmic Drugs and Drug Safety and Risk Management Advisory Committee Meeting, 2004.http://www.fda.gov/ohrms/dockets/ac/04/slides /4017S1_06_Pitts.ppt. Accessed August 15, 2013.
Conflict of Interest Disclosures: Dr Altman is a consultant to Ogilvy Health, an advertising agency that works with numerous dermatology-related products; however, none are related to this editorial.
6. NBC News online report by Associated Press, August 15, 2013. http://www.nbcnews.com/id /20041453/ns/health-pregnancy/t/some -accutaneusers-pregnant-despite-warning /#.UlknGFAkJ8E. Accessed August 15, 2013.
REFERENCES
7. Shin J, Cheetham TC, Wong L, et al. The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care system. J Am Acad Dermatol. 2011;65(6):1117-1125.
1. Henshaw SK. Unintended pregnancy in the United States. Fam Plann Perspect. 1998;30(1):24-29, 46. 2. US Food and Drug Administration. Accutane and pregnancy exposure. http://www.fda.gov/ohrms /dockets/ac/00/slides/3639s1c.pdf. Accessed August 15, 2013.
362
less understanding of effective contraceptive methods. The authors encourage clinicians to provide more information on the highly effective methods of contraception to help their female patients avoid fetal exposure to isotretinoin. In 2009, Kanelleas et al15 reported that none of the pregnancies that occurred in their patients during isotretinoin therapy could have been prevented by closer adherence to the guidelines of either the UK or US protocols. They suggested that parenteral progesterone only contraceptives, which are more than 99% effective and are independent of the patient’s individual compliance, be adopted as the standard approach to contraception for female patients considered for isotretinoin therapy. The idea that all women exposed to isotretinoin should use only contraception methods that are more than 99% effective in preventing pregnancy is a tempting one, because this would save much heartache to both the patients and their physicians. It is my opinion that providing all pros and cons of all available contraceptive methods and evaluating the patient’s non– isotretinoin-related risks in using such methods is outside the scope of a dermatology practice; however, it is definitely within the scope of our practice to provide clear information on the effectiveness and acceptable choices of various contraceptive methods and to refer our patients to knowledgeable OB-GYN colleagues for further evaluation and counseling. The message is loud and clear. If we want to retain the ability to use isotretinoin, an indispensable tool in our armamentarium, we have to find ways to increase adherence to contraceptive methods that will reduce and, hopefully, eliminate fetal exposure to isotretinoin. Yes, the responsibility for decreasing fetal exposure to isotretinoin lies on the shoulders of both the physician and the patient, but if we have avenues to improve on the numbers of pregnancies exposed to isotretinoin by better communication with our patients, we must take it.
3. Stern RS. Medication and medical service utilization for acne 1995-1998. J Am Acad Dermatol. 2000;43(6):1042-1048.
8. US Food and Drug Administration; Drug Safety and Risk Management Advisory Committee; Dermatologic and Ophthalmic Drugs Advisory Committee. Briefing document for iPledge year 1 update, 2007. http://www.fda.gov/ohrms/dockets /ac/07/briefing/2007-4311b1-02-ipledge.pdf. Accessed August 15, 2013.
4. The needless tragedies of Accutane. New York Times. May 12, 1988. http://www.nytimes.com
9. Perlman SE, Leach EE, Dominguez L, Ruszkowski AM, Rudy SJ. “Be smart, be safe, be
sure”: the revised Pregnancy Prevention Program for women on isotretinoin. J Reprod Med. 2001;46(2)(suppl):179-185. 10. Isaacs JN, Creinin MD. Miscommunication between healthcare providers and patients may result in unplanned pregnancies. Contraception. 2003;68(5):373-376. 11. Boucher N, Beaulac-Baillargeon L. Pregnancy prevention among women taking isotretinoin: failure to comply with the recommendations. Can Fam Physician. 2006;52:338-339. 12. Steinkellner A, Chen W, Denison SE. Adherence to oral contraception in women on Category X medications. Am J Med. 2010;123(10):929-934, e1. 13. Biggs MA, Foster DG. Misunderstanding the risk of conception from unprotected and protected sex. Women’s Health Issues. 2013;23(1):e47-e53. 14. Werner CA, Papic MJ, Ferris LK, et al. Women's experiences with isotretinoin risk reduction counseling [published online November 20, 2013]. JAMA Dermatol. doi:10.1001 /jamadermatol.2013.6862. 15. Kanelleas AI, Thornton S, Berth-Jones J. Suggestions for effective contraception in isotretinoin therapy. Br J Clin Pharmacol. 2009;67(1):137-138.
JAMA Dermatology April 2014 Volume 150, Number 4
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Georgetown University Medical Center User on 05/22/2015
jamadermatology.com
