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Compounded 17-hydroxyprogesterone caproate is an inexpensive and safe alternative to the FDA-approved product
Editorials
www.AJOG.org
Compounded 17-hydroxyprogesterone caproate is an inexpensive and safe alternative to the FDA-approved product Arnold W. Cohen, MD; Samuel Parry, MD
P
rematurity continues to be the major source of neonatal morbidity and mortality. Efforts to decrease the risk of prematurity in the past have focused on preventing contractions with tocolytics, early identification of contractions with home uterine monitoring, and predicting preterm delivery through history and biochemical evaluations. The Institute of Medicine estimated in 2005 that the average direct medical care costs for a preterm infant in the United States is $33,200, with the majority (85%) of this cost occurring in the first year of life.1 The cost per infant increases to $51,600 when maternal medical care costs ($3800), early intervention costs ($1203), special education costs ($2150), and lost household productivity costs ($11,215) are considered. The only markers for increased risk of preterm delivery that have reasonable positive predictive values in the asymptomatic patient are a history of preterm delivery and the finding on transvaginal ultrasound of a shortened cervix in a singleton gestation.2,3 Since the National Institutes of Healthesponsored trial published in the New England Journal of Medicine in 2003 by Meis et al,4 it has been accepted by the obstetrical community that those patients with a previous preterm delivery would benefit from weekly injections of 17-hydroxyprogesterone caproate (17P) starting at 16-20 weeks’ gestation and continuing until 36 weeks’ gestation. Because preterm delivery occurs in about 12% of all deliveries, it has been estimated that about 140,000 patients each year would be candidates for receiving 17P to reduce their risk of preterm birth. These patients account for about 30,000 preterm births, of which a third could be prevented by receiving 17P. This means that 14 patients are treated to prevent 1 preterm birth. The prevention of all 10,000 preterm births would result in direct medical cost savings of $330 million and total medical cost of more than $500 million.5 The value of any treatment that reduces preterm births is going to be related to the efficacy of the medication and the
From the Department of Obstetrics and Gynecology Albert Einstein Medical Center (Dr Cohen), and Department of Obstetrics and Gynecology, University of Pennsylvania (Dr Parry), Philadelphia, PA. The authors report no conflict of interest. Reprints not available from the author. 0002-9378/free ª 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.11.019
See related article, page 47
12 American Journal of Obstetrics & Gynecology JANUARY 2014
safety of the medication as well as its cost. In 2013, we have 2 choices: one a Food and Drug Administration (FDA)e approved drug and the other a compounded drug produced by special pharmacies regulated by the state. There have been no published data to suggest the efficacy of the compounded 17P is different from that of the FDA-approved drug. The FDA-approved drug costs $695 per injection ($13,900 per pregnancy); the compounded 17P costs about $15 per injection ($300 per pregnancy). When the cost to health care is calculated for 140,000 pregnancies using the FDA-approved drug, society is spending almost $2 billion to save $500 million (ie, spending $4 to save $1). When one uses the compounded 17P, society is spending $42 million to save $500 million, or more than a 10:1 return on its investment. The issue then becomes the safety of the medication being used. In this edition of the Journal, Chang et al6 demonstrated that compounded 17P obtained from 15 pharmacies throughout the United States did not raise safety concerns when assessed for potency, sterility, pyrogen status, or impurities. The research was supported by the Obstetrical-Fetal Pharmacology Research Units (OPRU) Network, which is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development to carry out pharmacology research to enhance the understanding of obstetrical pharmacokinetics and pharmacodynamics and improve therapeutics during pregnancy. To perform this analysis, the investigators contacted 20 maternal-fetal medicine specialists practicing in high-volume clinical centers throughout the United States, and 15 of these specialists identified 17 compounding pharmacies they use to fill their patients’ 17P prescriptions. Fifteen compounding pharmacies agreed to participate in the study by providing 17P samples for testing, and the investigators utilized state-ofthe-art technology to perform content and impurity analyses of the 17P compounds and testing for sterility and pyrogens (endotoxins). All compounded samples were within the acceptable range (90e110%) of declared potency on the label for the FDA-approved drug. Tests for impurities, endotoxins, and sterility were similarly encouraging. In general, the OPRU Network provides the expert infrastructure needed to test therapeutic drugs during pregnancy. Obstetrical pharmacology research has not been supported extensively by private pharmaceutical companies, so the OPRU Network addresses a critical, understudied area of obstetrical research. Over the past 2 years, OPRU Network investigators have published more than 30 original studies in peer-reviewed journals, including clinically relevant studies of
www.AJOG.org commonly used drugs such as 17P, nifedipine, and antenatal corticosteroids.7-12 In the study published in this month’s Journal, the OPRU-funded investigators were able to utilize their expertise and technical sophistication to perform the most extensive study to date of compounded 17P products and determine that compounded 17P did not raise safety concerns when compared with the FDA-approved product. We believe that it is critical for obstetrical providers to understand that the cost of compounded 17P is much lower than that of the FDA-approved product, and many patients will have limited access to the FDA-approved product based on their insurance coverage. The OPRU-funded study published by Chang et al6 in this edition of the Journal demonstrates that compounded 17P should provide an effective, safe, and inexpensive alternative for patients who require treatment with 17P. Of course, obstetrical providers are encouraged to evaluate the quality assurance procedures in place at pharmacies from which they prescribe 17P compounds. -
REFERENCES 1. Behrman RE, Butler AS. Preterm birth: causes, consequences, and prevention. Washington, DC: National Academies Press; 2006. 2. Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network. N Engl J Med 1996;334:567-72.
Editorials 3. Mercer BM, Goldenberg RL, Das A, et al. The preterm prediction study: a clinical risk assessment system. Am J Obstet Gynecol 1996;174: 1885-93; discussion 93-5. 4. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003;348:2379-85. 5. Armstrong J. Unintended consequences—the cost of preventing preterm births after FDA approval of a branded version of 17OHP. N Engl J Med 2011;364:1689-91. 6. Chang J, Zhao Y, Zhao W, et al; for the Obstetrical-Fetal Pharmacology Research Units Network. Quality assessment of compounded 17hydroxyprogesterone caproate. Am J Obstet Gynecol 2014;210:47.e1-7. 7. Caritis SN, Sharma S, Venkataramanan R, et al. Pharmacology and placental transport of 17-hydroxyprogesterone caproate in singleton gestation. Am J Obstet Gynecol 2012;207:398.e1-8. 8. Caritis SN, Zhao Y, Bettinger J, Venkataramanan R. Qualitative and quantitative measures of various compounded formulations of 17-alpha hydroxyprogesterone caproate. Am J Obstet Gynecol 2013;208:470. e1-5. 9. Cuppett CD, Zhao Y, Caritis S, Zhang S, Zhao W, Venkataramanan R. Effect of endogenous steroid hormones on 17-alpha-hydroxyprogesterone caproate metabolism. Am J Obstet Gynecol 2013;208:86.e1-6. 10. Haas DM, Dantzer J, Lehmann AS, et al. The impact of glucocorticoid polymorphisms on markers of neonatal respiratory disease after antenatal betamethasone administration. Am J Obstet Gynecol 2013;208:215. e1-6. 11. Haas DM, Lehmann AS, Skaar T, et al. The impact of drug metabolizing enzyme polymorphisms on outcomes after antenatal corticosteroid use. Am J Obstet Gynecol 2012;206:447.e17-24. 12. Haas DM, Quinney SK, Clay JM, et al. Nifedipine pharmacokinetics are influenced by CYP3A5 genotype when used as a preterm labor tocolytic. Am J Perinatol 2013;30:275-81.
JANUARY 2014 American Journal of Obstetrics & Gynecology
13
www.AJOG.org
Compounded 17-hydroxyprogesterone caproate is an inexpensive and safe alternative to the FDA-approved product Arnold W. Cohen, MD; Samuel Parry, MD
P
rematurity continues to be the major source of neonatal morbidity and mortality. Efforts to decrease the risk of prematurity in the past have focused on preventing contractions with tocolytics, early identification of contractions with home uterine monitoring, and predicting preterm delivery through history and biochemical evaluations. The Institute of Medicine estimated in 2005 that the average direct medical care costs for a preterm infant in the United States is $33,200, with the majority (85%) of this cost occurring in the first year of life.1 The cost per infant increases to $51,600 when maternal medical care costs ($3800), early intervention costs ($1203), special education costs ($2150), and lost household productivity costs ($11,215) are considered. The only markers for increased risk of preterm delivery that have reasonable positive predictive values in the asymptomatic patient are a history of preterm delivery and the finding on transvaginal ultrasound of a shortened cervix in a singleton gestation.2,3 Since the National Institutes of Healthesponsored trial published in the New England Journal of Medicine in 2003 by Meis et al,4 it has been accepted by the obstetrical community that those patients with a previous preterm delivery would benefit from weekly injections of 17-hydroxyprogesterone caproate (17P) starting at 16-20 weeks’ gestation and continuing until 36 weeks’ gestation. Because preterm delivery occurs in about 12% of all deliveries, it has been estimated that about 140,000 patients each year would be candidates for receiving 17P to reduce their risk of preterm birth. These patients account for about 30,000 preterm births, of which a third could be prevented by receiving 17P. This means that 14 patients are treated to prevent 1 preterm birth. The prevention of all 10,000 preterm births would result in direct medical cost savings of $330 million and total medical cost of more than $500 million.5 The value of any treatment that reduces preterm births is going to be related to the efficacy of the medication and the
From the Department of Obstetrics and Gynecology Albert Einstein Medical Center (Dr Cohen), and Department of Obstetrics and Gynecology, University of Pennsylvania (Dr Parry), Philadelphia, PA. The authors report no conflict of interest. Reprints not available from the author. 0002-9378/free ª 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.11.019
See related article, page 47
12 American Journal of Obstetrics & Gynecology JANUARY 2014
safety of the medication as well as its cost. In 2013, we have 2 choices: one a Food and Drug Administration (FDA)e approved drug and the other a compounded drug produced by special pharmacies regulated by the state. There have been no published data to suggest the efficacy of the compounded 17P is different from that of the FDA-approved drug. The FDA-approved drug costs $695 per injection ($13,900 per pregnancy); the compounded 17P costs about $15 per injection ($300 per pregnancy). When the cost to health care is calculated for 140,000 pregnancies using the FDA-approved drug, society is spending almost $2 billion to save $500 million (ie, spending $4 to save $1). When one uses the compounded 17P, society is spending $42 million to save $500 million, or more than a 10:1 return on its investment. The issue then becomes the safety of the medication being used. In this edition of the Journal, Chang et al6 demonstrated that compounded 17P obtained from 15 pharmacies throughout the United States did not raise safety concerns when assessed for potency, sterility, pyrogen status, or impurities. The research was supported by the Obstetrical-Fetal Pharmacology Research Units (OPRU) Network, which is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development to carry out pharmacology research to enhance the understanding of obstetrical pharmacokinetics and pharmacodynamics and improve therapeutics during pregnancy. To perform this analysis, the investigators contacted 20 maternal-fetal medicine specialists practicing in high-volume clinical centers throughout the United States, and 15 of these specialists identified 17 compounding pharmacies they use to fill their patients’ 17P prescriptions. Fifteen compounding pharmacies agreed to participate in the study by providing 17P samples for testing, and the investigators utilized state-ofthe-art technology to perform content and impurity analyses of the 17P compounds and testing for sterility and pyrogens (endotoxins). All compounded samples were within the acceptable range (90e110%) of declared potency on the label for the FDA-approved drug. Tests for impurities, endotoxins, and sterility were similarly encouraging. In general, the OPRU Network provides the expert infrastructure needed to test therapeutic drugs during pregnancy. Obstetrical pharmacology research has not been supported extensively by private pharmaceutical companies, so the OPRU Network addresses a critical, understudied area of obstetrical research. Over the past 2 years, OPRU Network investigators have published more than 30 original studies in peer-reviewed journals, including clinically relevant studies of
www.AJOG.org commonly used drugs such as 17P, nifedipine, and antenatal corticosteroids.7-12 In the study published in this month’s Journal, the OPRU-funded investigators were able to utilize their expertise and technical sophistication to perform the most extensive study to date of compounded 17P products and determine that compounded 17P did not raise safety concerns when compared with the FDA-approved product. We believe that it is critical for obstetrical providers to understand that the cost of compounded 17P is much lower than that of the FDA-approved product, and many patients will have limited access to the FDA-approved product based on their insurance coverage. The OPRU-funded study published by Chang et al6 in this edition of the Journal demonstrates that compounded 17P should provide an effective, safe, and inexpensive alternative for patients who require treatment with 17P. Of course, obstetrical providers are encouraged to evaluate the quality assurance procedures in place at pharmacies from which they prescribe 17P compounds. -
REFERENCES 1. Behrman RE, Butler AS. Preterm birth: causes, consequences, and prevention. Washington, DC: National Academies Press; 2006. 2. Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network. N Engl J Med 1996;334:567-72.
Editorials 3. Mercer BM, Goldenberg RL, Das A, et al. The preterm prediction study: a clinical risk assessment system. Am J Obstet Gynecol 1996;174: 1885-93; discussion 93-5. 4. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003;348:2379-85. 5. Armstrong J. Unintended consequences—the cost of preventing preterm births after FDA approval of a branded version of 17OHP. N Engl J Med 2011;364:1689-91. 6. Chang J, Zhao Y, Zhao W, et al; for the Obstetrical-Fetal Pharmacology Research Units Network. Quality assessment of compounded 17hydroxyprogesterone caproate. Am J Obstet Gynecol 2014;210:47.e1-7. 7. Caritis SN, Sharma S, Venkataramanan R, et al. Pharmacology and placental transport of 17-hydroxyprogesterone caproate in singleton gestation. Am J Obstet Gynecol 2012;207:398.e1-8. 8. Caritis SN, Zhao Y, Bettinger J, Venkataramanan R. Qualitative and quantitative measures of various compounded formulations of 17-alpha hydroxyprogesterone caproate. Am J Obstet Gynecol 2013;208:470. e1-5. 9. Cuppett CD, Zhao Y, Caritis S, Zhang S, Zhao W, Venkataramanan R. Effect of endogenous steroid hormones on 17-alpha-hydroxyprogesterone caproate metabolism. Am J Obstet Gynecol 2013;208:86.e1-6. 10. Haas DM, Dantzer J, Lehmann AS, et al. The impact of glucocorticoid polymorphisms on markers of neonatal respiratory disease after antenatal betamethasone administration. Am J Obstet Gynecol 2013;208:215. e1-6. 11. Haas DM, Lehmann AS, Skaar T, et al. The impact of drug metabolizing enzyme polymorphisms on outcomes after antenatal corticosteroid use. Am J Obstet Gynecol 2012;206:447.e17-24. 12. Haas DM, Quinney SK, Clay JM, et al. Nifedipine pharmacokinetics are influenced by CYP3A5 genotype when used as a preterm labor tocolytic. Am J Perinatol 2013;30:275-81.
JANUARY 2014 American Journal of Obstetrics & Gynecology
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