- Email: [email protected]
Response to the questions submitted by Mr. Reichmann
G Model
ARTICLE IN PRESS
RTX-7399; No. of Pages 1
Reproductive Toxicology xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox
Response to the questions submitted by Mr. Reichmann Dear Editor, This letter is in response to the questions submitted by Mr. Reichmann concerning the maternal and fetal safety of administering 32 mg of Zofran via continuous subcutaneous infusion pump over a 24-h period. Our study, “Ondansetron in pregnancy and risk of fetal outcomes in the United States” did not present information which specifically addressed administration of ondansetron using a subcutaneous pump. A study of the safety of high dose ondansetron administered through a pump is unlikely to be completed given the number of exposures required to evaluate relatively rare cardiac outcomes. With this in mind, we have to make do with the information we currently have: a subset of our study participants did self-report on ondansetron dose, duration, and timing. Among 466 women who took ondansetron in their first pregnancy, 191 (41%) reported the dose, duration, and timing. We do not have information on whether the administration was oral or by subcutaneous infusion. Among the 191 reports, 33 women (17%) reported a dose greater than or equal to 32 mg per day for a minimum duration of 6 weeks. Among these 33 women, 31 (94%) women took ondansetron in the first trimester, 32 (97%) in the second trimester, and 25 (76%) in the third trimester. Twenty-three (70%) women reported taking the high dose of ondansetron in all 3 trimesters. Maternal heart problems were part of our survey and none of the 33 women reported having a diagnosis of a major heart problem during the pregnancy. In the free-response section on side effects, one woman reported severe heart palpitations in response to Phenergan (promethazine). Another reported the same for Maxalon (metoclopramide) and a third reported an irregular heartbeat while taking ondansetron, Phenergan, Protonix, and antihistamines while on total parenteral nutrition. No maternal cardiovascular issues were reported specifically for ondansetron. Constipation was reported in 10 (30%) of the 33 women taking more than or equal to 32 mg of ondansetron per day, ranging from mild to severe constipation requiring enema. Only 3 (9%) of the 33 women reported ondansetron to be ineffective in treating their nausea and vomiting. There were 2 birth defects reported among the 33 women taking the high dose of ondansetron, a heart murmur and a metatarsus adductus defect. Currently there is no significant evidence to support a fetal or maternal cardiac risk to high dose, prolonged ondansetron use in pregnancy. The above data suggests many women are taking more than or equal to 32 mg of ondansetron per day for a significant
length of time without associated cardiac complications. Additionally, there are no case reports in the literature of cardiac problems following the use of 32 mg of ondansetron administered over a 24-h period in pregnant women. The absence of an identified cardiac risk must be taken into consideration when discussing the high effectiveness of ondansetron in the treatment of nausea and vomiting in pregnancy. If left untreated or inadequately treated, nausea and vomiting of pregnancy can lead to prolonged malnutrition, dehydration in pregnancy and adverse maternal and fetal outcomes. These include increased risks of therapeutic termination, premature labor/delivery, small birth weight infants, neurodevelopmental delay, and maternal post-traumatic stress. Again, given that a powered clinical trial of high-dose ondansetron is unlikely, a reasonable solution would be to require physicians to report maternal and fetal outcomes for all medications prescribed offlabel. Until then, we conclude that benefits of prolonged, high dose ondansetron with regular monitoring/treatment for constipation and electrolyte imbalance may outweigh the currently unproven risks in women who do not respond to a lower dosing schedule. This suggestion should be taken on a case-by-case basis depending on the physical condition of each patient. Marlena Fejzo a,b,∗ Keck School of Medicine, University of Southern California, Department of Maternal-Fetal Medicine, Los Angeles, CA, USA b David Geffen School of Medicine, University of California, Los Angeles, CA, USA a
Kimber MacGibbon HER Foundation, Damascus, OR, USA Patrick Mullin Keck School of Medicine, University of Southern California, Department of Maternal-Fetal Medicine, Los Angeles, CA, USA ∗ Corresponding author at: Keck School of Medicine, University of Southern California, Department of Maternal-Fetal Medicine, Los Angeles, CA, USA. E-mail address: [email protected] (M. Fejzo)
18 July 2016 21 September 2016 Available online xxx
http://dx.doi.org/10.1016/j.reprotox.2016.09.011 0890-6238/© 2016 Published by Elsevier Inc.
Please cite this article in press as: M. Fejzo, et al., Response to the questions submitted by Mr. Reichmann, Reprod Toxicol (2016), http://dx.doi.org/10.1016/j.reprotox.2016.09.011
ARTICLE IN PRESS
RTX-7399; No. of Pages 1
Reproductive Toxicology xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox
Response to the questions submitted by Mr. Reichmann Dear Editor, This letter is in response to the questions submitted by Mr. Reichmann concerning the maternal and fetal safety of administering 32 mg of Zofran via continuous subcutaneous infusion pump over a 24-h period. Our study, “Ondansetron in pregnancy and risk of fetal outcomes in the United States” did not present information which specifically addressed administration of ondansetron using a subcutaneous pump. A study of the safety of high dose ondansetron administered through a pump is unlikely to be completed given the number of exposures required to evaluate relatively rare cardiac outcomes. With this in mind, we have to make do with the information we currently have: a subset of our study participants did self-report on ondansetron dose, duration, and timing. Among 466 women who took ondansetron in their first pregnancy, 191 (41%) reported the dose, duration, and timing. We do not have information on whether the administration was oral or by subcutaneous infusion. Among the 191 reports, 33 women (17%) reported a dose greater than or equal to 32 mg per day for a minimum duration of 6 weeks. Among these 33 women, 31 (94%) women took ondansetron in the first trimester, 32 (97%) in the second trimester, and 25 (76%) in the third trimester. Twenty-three (70%) women reported taking the high dose of ondansetron in all 3 trimesters. Maternal heart problems were part of our survey and none of the 33 women reported having a diagnosis of a major heart problem during the pregnancy. In the free-response section on side effects, one woman reported severe heart palpitations in response to Phenergan (promethazine). Another reported the same for Maxalon (metoclopramide) and a third reported an irregular heartbeat while taking ondansetron, Phenergan, Protonix, and antihistamines while on total parenteral nutrition. No maternal cardiovascular issues were reported specifically for ondansetron. Constipation was reported in 10 (30%) of the 33 women taking more than or equal to 32 mg of ondansetron per day, ranging from mild to severe constipation requiring enema. Only 3 (9%) of the 33 women reported ondansetron to be ineffective in treating their nausea and vomiting. There were 2 birth defects reported among the 33 women taking the high dose of ondansetron, a heart murmur and a metatarsus adductus defect. Currently there is no significant evidence to support a fetal or maternal cardiac risk to high dose, prolonged ondansetron use in pregnancy. The above data suggests many women are taking more than or equal to 32 mg of ondansetron per day for a significant
length of time without associated cardiac complications. Additionally, there are no case reports in the literature of cardiac problems following the use of 32 mg of ondansetron administered over a 24-h period in pregnant women. The absence of an identified cardiac risk must be taken into consideration when discussing the high effectiveness of ondansetron in the treatment of nausea and vomiting in pregnancy. If left untreated or inadequately treated, nausea and vomiting of pregnancy can lead to prolonged malnutrition, dehydration in pregnancy and adverse maternal and fetal outcomes. These include increased risks of therapeutic termination, premature labor/delivery, small birth weight infants, neurodevelopmental delay, and maternal post-traumatic stress. Again, given that a powered clinical trial of high-dose ondansetron is unlikely, a reasonable solution would be to require physicians to report maternal and fetal outcomes for all medications prescribed offlabel. Until then, we conclude that benefits of prolonged, high dose ondansetron with regular monitoring/treatment for constipation and electrolyte imbalance may outweigh the currently unproven risks in women who do not respond to a lower dosing schedule. This suggestion should be taken on a case-by-case basis depending on the physical condition of each patient. Marlena Fejzo a,b,∗ Keck School of Medicine, University of Southern California, Department of Maternal-Fetal Medicine, Los Angeles, CA, USA b David Geffen School of Medicine, University of California, Los Angeles, CA, USA a
Kimber MacGibbon HER Foundation, Damascus, OR, USA Patrick Mullin Keck School of Medicine, University of Southern California, Department of Maternal-Fetal Medicine, Los Angeles, CA, USA ∗ Corresponding author at: Keck School of Medicine, University of Southern California, Department of Maternal-Fetal Medicine, Los Angeles, CA, USA. E-mail address: [email protected] (M. Fejzo)
18 July 2016 21 September 2016 Available online xxx
http://dx.doi.org/10.1016/j.reprotox.2016.09.011 0890-6238/© 2016 Published by Elsevier Inc.
Please cite this article in press as: M. Fejzo, et al., Response to the questions submitted by Mr. Reichmann, Reprod Toxicol (2016), http://dx.doi.org/10.1016/j.reprotox.2016.09.011