Generic and Brand-Name L-Thyroxine Are Not Bioequivalent for Children With Severe Congenital Hypothyroidism
Harvard University, Cambridge, Massachusetts, United StatesThe Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 12/2012; 98(2). DOI: 10.1210/jc.2012-3125
Context:In the United States, generic substitution of levothyroxine (l-T(4)) by pharmacists is permitted if the formulations are deemed to be bioequivalent by the Federal Drug Administration, but there is widespread concern that the pharmacokinetic standard used is too insensitive.Objective:We aimed to evaluate the bioequivalence of a brand-name l-T(4) (Synthroid) and an AB-rated generic formulation (Sandoz, Princeton, NJ) in children with severe hypothyroidism.Design:This was a prospective randomized crossover study in which patients received 8 weeks of one l-T(4) formulation followed by 8 weeks of the other.Setting:The setting was an academic medical center.Patients:Of 31 children with an initial serum TSH concentration >100 mU/L, 20 had congenital hypothyroidism (CH), and 11 had autoimmune thyroiditis.Main Outcome Measures:The primary endpoint was the serum TSH concentration. Secondary endpoints were the free T(4) and total T(3) concentrations.Results:The serum TSH concentration was significantly lower after 8 weeks of Synthroid than after generic drug (P = .002), but thyroid hormone levels did not differ significantly. Subgroup analysis revealed that the difference in TSH was restricted to patients with CH (P = .0005). Patients with CH required a higher l-T(4) dose (P < .0004) and were younger (P = .003) but were not resistant to thyroid hormone; 15 of 16 CH patients had severe thyroid dysgenesis or agenesis on imaging. The response to generic vs brand-name preparation remained significant when adjusted for age.Conclusions:Synthroid and an AB-rated generic l-T(4) are not bioequivalent for patients with severe hypothyroidism due to CH, probably because of diminished thyroid reserve. It would therefore seem prudent not to substitute l-T(4) formulations in patients with severe CH, particularly in those <3 yr of age. Our results may have important implications for other severely hypothyroid patients in whom precise titration of l-T(4) is necessary.
- The Journal of Clinical Endocrinology and Metabolism 02/2013; 98(2):511-4. DOI:10.1210/jc.2012-4310 · 6.21 Impact Factor
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ABSTRACT: Biochemical screening of neonates for congenital hypothyroidism permits early initiation of levothyroxine treatment and thus prevents the development of intellectual disability. Two novel studies now address whether brand-name and generic levothyroxine are interchangeable in this context.Nature Reviews Endocrinology 03/2013; 9(5). DOI:10.1038/nrendo.2013.46 · 13.28 Impact Factor
Article: Hypothyroidism in the newborn period[Show abstract] [Hide abstract]
ABSTRACT: This review summarizes significant advances in the epidemiology, pathophysiology and treatment of congenital hypothyroidism, with a focus on thyroid dysfunction in preterm infants. Congenital hypothyroidism appears to be increasing in incidence, primarily due to increased stringency of screening strategies, with smaller contributions from changing demographics and improved survival of increasingly premature infants. The greatest increase has been in mildly affected infants. Although many such cases are transient, some eventually prove to be severe and/or permanent. In preterm infants, transient hypothyroidism is common and may be delayed in onset. The cause is probably multifactorial, and inadequate iodine intake may contribute to some cases. Transient hypothyroxinemia of prematurity, also common in premature infants, is correlated with markers of inflammation. Despite concern about the potential morbidity of transient hypothyroxinemia of prematurity, the benefits and safety of treatment have not been established. Novel genetic causes of congenital hypothyroidism continue to be identified, and accumulating data support the sensitivity of infants with severe congenital hypothyroidism to small changes in levothyroxine formulation. Changes in newborn screening strategies have increasingly identified thyroid function abnormalities of unclear clinical significance. Novel causes of congenital hypothyroidism continue to be identified, and new data continue to emerge regarding optimal therapy.Current opinion in endocrinology, diabetes, and obesity 08/2013; 20(5). DOI:10.1097/01.med.0000433063.78799.c2 · 3.37 Impact Factor
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