2.
3.
4.
5.
6.
7.
8.
stimulation surgery among insured elders with Parkinson disease. Neurology 2014;82:163–171. Wright Willis A, Evanoff BA, Lian M, Criswell SR, Racette BA. Geographic and ethnic variation in Parkinson disease: a population-based study of US Medicare beneficiaries. Neuroepidemiology 2010;34:143–151. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence and distribution of parkinsonism in Olmsted County, Minnesota, 1976–1990. Neurology 1999;52: 1214–1220. Benito-Leon J, Bermejo-Pareja F, Morales-Gonzalez JM, et al. Incidence of Parkinson disease and parkinsonism in three elderly populations of central Spain. Neurology 2004; 62:734–741. Baldereschi M, Di Carlo A, Rocca WA, et al; for the ILSA Working Group. Parkinson’s disease and parkinsonism in a longitudinal study: two-fold higher incidence in men. Neurology 2000;55:1358–1363. Centers for Medicare and Medicaid Services. Variation of Part D Enrollment by Race, Age, Gender and State. 5-192014. https://www.ccwdata.org/web/guest/medicare-charts/ medicare-part-d-charts. Zijlmans JC, Katzenschlager R, Daniel SE, Lees AJ. The L-dopa response in vascular parkinsonism. J Neurol Neurosurg Psychiatry 2004;75:545–547. Constantinescu R, Richard I, Kurlan R. Levodopa responsiveness in disorders with parkinsonism: a review of the literature. Mov Disord 2007;22:2141–2148.
THE PILL TIMES 2: WHAT EVERY WOMAN WITH MULTIPLE SCLEROSIS SHOULD KNOW
Lily Jung Henson, Seattle; Steven Cavalier, Cambridge, MA: The editorial by Dr. LangerGould1 included misleading statements about teriflunomide. Human data for teriflunomide are available. Teriflunomide is the active metabolite of leflunomide. Animal studies demonstrated a risk of teratogenicity for both. However, a prospective trial of leflunomide,2 confirmed by over 2.3 million patient-years of postmarketing exposure, showed no increased risk for major birth defects, major or minor anomalies, or spontaneous abortions. Similarly, in the teriflunomide clinical program (greater than 12 years and greater than 6,800 patient-years of exposure), all newborns were healthy without structural or functional abnormalities, and the spontaneous abortion rate was similar to that of the general population. Dr. Langer-Gould recommended stopping teriflunomide 2 years prior to conception. This is not
aligned with the approved labeling for teriflunomide that states “pregnancy should be avoided prior to completion of an accelerated elimination procedure” without any mention of a suggested waiting period.3 An accelerated elimination procedure can clear teriflunomide within 11 days to a plasma concentration less than 0.02 mcg/mL, predicted to have minimal risk to the fetus. Author Response: Annette M. Langer-Gould, Pasadena, CA: I thank Drs. Henson and Cavalier for their comments on my editorial.1 Teriflunomide (the active metabolite of leflunomide) is teratogenic and embryotoxic in animal models and no convincing data exist that exposure during pregnancy is safe. It is not possible that the 2.3 million patient-years pertain to pregnancy exposures. The published literature includes approximately 100 pregnancies with accidental exposure. The “prospective trial” cited is a volunteer call-in registry fraught with bias, albeit with rigorous methods for assessing malformations.2 This study reported 56 live births from 64 women with an average of only 3 weeks of postconception leflunomide exposure, of which 95% underwent the rapid elimination procedure. Three of the 56 (5.4%) offspring had major structural defects, 47% had 3 or more minor structural anomalies, and 35.7% were delivered preterm.2 Exposed infants were also significantly smaller at birth and postnatally. After adjusting for some confounders, the p values in this underpowered study were .0.05. This is not evidence that accidental exposure during pregnancy even with rapid elimination is safe. The recommendation is that a woman on teriflunomide desiring pregnancy should stop medication until a safe leflunomide blood level is reached either by natural elimination (;2 years) or a rapid elimination procedure. © 2014 American Academy of Neurology 1.
2.
3.
Langer-Gould AM. The pill times 2: what every woman with multiple sclerosis should know. Neurology 2014;82: 654–655. Chambers CD, Johnson DL, Robinson LK, et al. Birth outcomes in women who have taken leflunomide during pregnancy. Arthritis Rheum 2010;62:1494–1503. Food and Drug Administration. Teriflunomide package insert: revised September 2012. Silver Spring, MD: Food and Drug Administration; 2012.
Author disclosures are available upon request ([email protected]). Neurology 83
October 28, 2014
1685
3.
4.
5.
6.
7.
8.
stimulation surgery among insured elders with Parkinson disease. Neurology 2014;82:163–171. Wright Willis A, Evanoff BA, Lian M, Criswell SR, Racette BA. Geographic and ethnic variation in Parkinson disease: a population-based study of US Medicare beneficiaries. Neuroepidemiology 2010;34:143–151. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence and distribution of parkinsonism in Olmsted County, Minnesota, 1976–1990. Neurology 1999;52: 1214–1220. Benito-Leon J, Bermejo-Pareja F, Morales-Gonzalez JM, et al. Incidence of Parkinson disease and parkinsonism in three elderly populations of central Spain. Neurology 2004; 62:734–741. Baldereschi M, Di Carlo A, Rocca WA, et al; for the ILSA Working Group. Parkinson’s disease and parkinsonism in a longitudinal study: two-fold higher incidence in men. Neurology 2000;55:1358–1363. Centers for Medicare and Medicaid Services. Variation of Part D Enrollment by Race, Age, Gender and State. 5-192014. https://www.ccwdata.org/web/guest/medicare-charts/ medicare-part-d-charts. Zijlmans JC, Katzenschlager R, Daniel SE, Lees AJ. The L-dopa response in vascular parkinsonism. J Neurol Neurosurg Psychiatry 2004;75:545–547. Constantinescu R, Richard I, Kurlan R. Levodopa responsiveness in disorders with parkinsonism: a review of the literature. Mov Disord 2007;22:2141–2148.
THE PILL TIMES 2: WHAT EVERY WOMAN WITH MULTIPLE SCLEROSIS SHOULD KNOW
Lily Jung Henson, Seattle; Steven Cavalier, Cambridge, MA: The editorial by Dr. LangerGould1 included misleading statements about teriflunomide. Human data for teriflunomide are available. Teriflunomide is the active metabolite of leflunomide. Animal studies demonstrated a risk of teratogenicity for both. However, a prospective trial of leflunomide,2 confirmed by over 2.3 million patient-years of postmarketing exposure, showed no increased risk for major birth defects, major or minor anomalies, or spontaneous abortions. Similarly, in the teriflunomide clinical program (greater than 12 years and greater than 6,800 patient-years of exposure), all newborns were healthy without structural or functional abnormalities, and the spontaneous abortion rate was similar to that of the general population. Dr. Langer-Gould recommended stopping teriflunomide 2 years prior to conception. This is not
aligned with the approved labeling for teriflunomide that states “pregnancy should be avoided prior to completion of an accelerated elimination procedure” without any mention of a suggested waiting period.3 An accelerated elimination procedure can clear teriflunomide within 11 days to a plasma concentration less than 0.02 mcg/mL, predicted to have minimal risk to the fetus. Author Response: Annette M. Langer-Gould, Pasadena, CA: I thank Drs. Henson and Cavalier for their comments on my editorial.1 Teriflunomide (the active metabolite of leflunomide) is teratogenic and embryotoxic in animal models and no convincing data exist that exposure during pregnancy is safe. It is not possible that the 2.3 million patient-years pertain to pregnancy exposures. The published literature includes approximately 100 pregnancies with accidental exposure. The “prospective trial” cited is a volunteer call-in registry fraught with bias, albeit with rigorous methods for assessing malformations.2 This study reported 56 live births from 64 women with an average of only 3 weeks of postconception leflunomide exposure, of which 95% underwent the rapid elimination procedure. Three of the 56 (5.4%) offspring had major structural defects, 47% had 3 or more minor structural anomalies, and 35.7% were delivered preterm.2 Exposed infants were also significantly smaller at birth and postnatally. After adjusting for some confounders, the p values in this underpowered study were .0.05. This is not evidence that accidental exposure during pregnancy even with rapid elimination is safe. The recommendation is that a woman on teriflunomide desiring pregnancy should stop medication until a safe leflunomide blood level is reached either by natural elimination (;2 years) or a rapid elimination procedure. © 2014 American Academy of Neurology 1.
2.
3.
Langer-Gould AM. The pill times 2: what every woman with multiple sclerosis should know. Neurology 2014;82: 654–655. Chambers CD, Johnson DL, Robinson LK, et al. Birth outcomes in women who have taken leflunomide during pregnancy. Arthritis Rheum 2010;62:1494–1503. Food and Drug Administration. Teriflunomide package insert: revised September 2012. Silver Spring, MD: Food and Drug Administration; 2012.
Author disclosures are available upon request ([email protected]). Neurology 83
October 28, 2014
1685
